i-viii cshperspectmed-PKD-FM 1. · Drosophilaas a Model to Study Mitochondrial Dysfunction in Parkinson’s Disease, 275 Ming Guo Mitochondrial Biology and Parkinson’s Disease,

Parkinson’s Disease

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Parkinson’s DiseaseA subject collection from Cold Spring Harbor Perspectives in Medicine

EDITED BY

Serge PrzedborskiColumbia University

COLD SPRING HARBOR LABORATORY PRESS

Cold Spring Harbor, New York † www.cshlpress.org


Parkinson’s DiseaseA Subject Collection from Cold Spring Harbor Perspectives in MedicineArticles online at www.perspectivesinmedicine.org

All rights reserved# 2012 by Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New YorkPrinted in the United States of America

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Front cover artwork: Putamen in the brain. Computer artwork of a person’s head showing thebrain inside. The highlighted area (center) shows the putamen, which is located at the base ofthe forebrain (telencephalon). The main function of the putamen is to regulate movements andinfluence learning. It does this through the regulation of the neurotransmitter dopamine. Assuch it plays a role in degenerative neurological disorders, such as Parkinson’s disease, whichare thought to be linked to a decrease in the production or effect of dopamine. Photo fromRoger Harris/Photo Researchers, Inc.

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Parkinson’s disease / edited by Serge Przedborski.p.; cm.

”A subject collection from Cold Spring Harbor perspectives in medicine”.Includes bibliographical references and index.ISBN 978-1-936113-32-3 (hardcover : alk. paper)I. Przedborski, Serge. II. Cold Spring Harbor perspectives in medicine.[DNLM: 1. Parkinson Disease--genetics--Collected Works. 2. Parkinson Disease--

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Contents

Preface, vii

The History of Parkinson’s Disease: Early Clinical Descriptions and Neurological

Therapies, 1

Christopher G. Goetz

Clinical Approach to Parkinson’s Disease: Features, Diagnosis, and Principles

of Management, 17

Joao Massano and Kailash P. Bhatia

Parkinson’s Disease and Parkinsonism: Neuropathology, 33

Dennis W. Dickson

Genetics of Parkinson’s Disease, 49

Christine Klein and Ana Westenberger

a-Synuclein in Parkinson’s Disease, 65

Leonidas Stefanis

Leucine-Rich Repeat Kinase 2 for Beginners: Six Key Questions, 89

Lauren R. Kett and William T. Dauer

Parkinsonism Due to Mutations in PINK1, Parkin, and DJ-1 and Oxidative Stress

and Mitochondrial Pathways, 99

Mark R. Cookson

Genomics and Bioinformatics of Parkinson’s Disease, 111

Sonja W. Scholz, Tim Mhyre, Habtom Ressom, Salim Shah, and Howard J. Federoff

Parkinson’s Disease: Gene Therapies, 127

Philippe G. Coune, Bernard L. Schneider, and Patrick Aebischer

Functional Neuroanatomy of the Basal Ganglia, 143

Jose L. Lanciego, Natasha Luquin, and Jose A. Obeso

Functional Neuroimaging in Parkinson’s Disease, 163

Martin Niethammer, Andrew Feigin, and David Eidelberg

Motor Control Abnormalities in Parkinson’s Disease, 185

Pietro Mazzoni, Britne Shabbott, and Juan Camilo Cortes

v


Physiological Phenotype and Vulnerability in Parkinson’s Disease, 203

D. James Surmeier, Jaime N. Guzman, Javier Sanchez, and Paul T. Schumacker

Modeling Parkinson’s Disease in Primates: The MPTP Model, 231

Gregory Porras, Qin Li, and Erwan Bezard

A Guide to Neurotoxic Animal Models of Parkinson’s Disease, 241

Kim Tieu

Animal Models of Parkinson’s Disease: Vertebrate Genetics, 261

Yunjong Lee, Valina L. Dawson, and Ted M. Dawson

Drosophila as a Model to Study Mitochondrial Dysfunction in

Parkinson’s Disease, 275

Ming Guo

Mitochondrial Biology and Parkinson’s Disease, 293

Celine Perier and Miquel Vila

The Role of Autophagy in Parkinson’s Disease, 313

Melinda A. Lynch-Day, Kai Mao, Ke Wang, Mantong Zhao, and Daniel J. Klionsky

Disruption of Protein Quality Control in Parkinson’s Disease, 327

Casey Cook, Caroline Stetler, and Leonard Petrucelli

Programmed Cell Death in Parkinson’s Disease, 345

Katerina Venderova and David S. Park

Innate Inflammation in Parkinson’s Disease, 369

V. Hugh Perry

Inflammation and Adaptive Immunity in Parkinson’s Disease, 381

R. Lee Mosely, Jessica A. Hutter-Saunders, David K. Stone, and Howard E. Gendelman

Index, 399

Contents

vi


Preface

PARKINSON’S DISEASE (PD) WAS ONCE A TABOO SUBJECT as affected individuals made every effort tohide the physical manifestations of their movement disorder. This is no longer true. Rather

than hiding their affliction, politicians, artists, and world leaders with PD openly admit to theirmedical condition and discuss how they cope with the medical, social, and emotional challenges.Yet, the reality is that if today the public awareness of PD runs very high, our understanding ofwhy and how the disease occurs and progresses lags behind. For every stone turned, clinical andbasic researchers in the field of PD find many unturned.

If we are to devise effective therapies for this disabling disorder, we must first crack the neurobiol-ogy of PD; to do so will require recruiting talented individuals with different skill sets and visions towork in a multidisciplinary manner on the outstanding questions that still plague the field. Cliniciansmust be encouraged to be exposed to the basic physiology and the molecular and cellular biology ofPD and, conversely, basic researchers must be exposed to the finer clinical aspects of PD.

I often hear from colleagues, both clinicians and basic scientists, who would like to join theresearch effort in PD, “What can I read to educate myself to the disease and the issues surroundingits neurobiology and treatment?” My colleagues in basic science often express frustration in readingclinical textbooks on the subject, because they are too cryptic and detailed for nonclinicians, and,conversely, my clinician friends are often stymied by the technical jargon and concepts that litterthe pages of basic science books. I was often left wondering whether I could recommend a singlebook on PD to both sets of colleagues, but thus far I have been unable to identify one. Such abook would be designed specifically to bridge the clinical and basic science aspects of PD underone cover: It would be more like a textbook describing the forest rather than an overwhelmingcompendium describing all of the individual trees (and even branches), and it would present funda-mental and practical information to the reader, but as a didactic tool with editorializing from eachauthor, aimed at providing take-home messages and pointers.

It was with these ideas in mind that the Cold Spring Harbor Laboratory Press agreed to embarkwith me on the editing of this mini-textbook on bench-to-bedside understanding of PD. Each expertwho agreed to contribute to this book was asked to write a chapter as if they were thinking about whatthey would say to a new student or faculty member interested in working on PD, irrespective ofwhether he/she was a basic scientist or a clinician.

Thus, readers will start their journey with the history of PD (Goetz), to set the stage and under-stand what PD is and how this neurological disorder was initially defined and identified. From there,chapters by Massano and Bhatia and by Dickson provide the clinical and neuropathological bases ofthis disease. Among other things, they stress the fact that the clinical features of PD are not limited toPD per se, but can be shared by roughly 40 different clinical conditions. Moreover, these chapters alsopoint out that even though PD is essentially known for its motor manifestations and the loss of dopa-minergic neurons, a plethora of nonmotor features also exists and nondopaminergic neurons alsodegenerate, all of which play a critical role in the overall expression of PD and ensuing disability.

As with other prominent adult-onset neurodegenerative conditions such as Alzheimer’s diseaseand amyotrophic lateral sclerosis, PD presents itself essentially as a sporadic condition, but in ahandful of cases, PD can be familial. In these rare instances, the PD-like phenotype is inheritedeither as a dominant or recessive trait and has been linked to a variety of mutations in seemingly dis-parate genes. All of these rare genetic forms of PD are under intense scrutiny because of the

vii


expectation that a better understanding of the normal roles of the gene products, and how mutationsaffect these functions, may provide important hints into the neurobiology of sporadic PD. Severalchapters are thus dedicated to the familial forms of PD, first with the introduction to PD geneticsfrom Klein and Westenberger and then with different chapters on selected genes linked to PD includ-ing a-synuclein (Stefanis), LRRK2 (Kett and Dauer), and PINK1/Parkin/DJ-1 (Cookson). Thegenetic chapters culminate in two important discussions: one by Scholz et al. on the unbiasedapproaches to genetics, which are becoming more popular in an attempt to tease out disease mech-anisms, and the other by Coune et al. on gene therapies.

Aside from the actual mechanisms responsible for or contributing to the loss of specific types ofneurons in PD, the degenerative process alters the chemical neuroanatomy of the basal ganglia, whichunderpins the expression of many of the motor abnormalities shown by PD patients. To discuss thisimportant topic, Lanciego et al., Neithammer et al., and Mazzoni et al. start at the level of the patientsand explore the neurochemical circuitry using functional neuroanatomy, brain imaging, and electro-physiology to provide a macroscopic view of the disease. A subsequent chapter by Surmeier et al. thendiscusses a more fine-grained approach to PD microscopical functional imaging techniques tofurther define the basal ganglia circuitry that is the target of the neurodegenerative process. A keyquestion addressed by this type of research is why some neurons are more susceptible than othersto the degenerative process in PD.

Most PD researchers interested in probing the neurobiology of this disorder rely heavily on theuse of experimental models. Thus, with the series of chapters authored by Porras et al., Tieu, Leeet al., and Guo, the topic of PD modeling is covered from primate to invertebrate models andfrom genetic to toxic models.

The final chapters (Perier and Vila, Lynch-Day et al., Cook et al., Venderova and Park, Perry, andMosely et al.) are dedicated to emerging and seemingly important pathogenic mechanisms inPD; among the selected topics are the roles that mitochondria, autophagy, protein quality control,programmed cell death, and neuroinflammation play in the disease process.

This is the outline of the book. Yet, before starting, I would like to add one more thing: Fastenyour seatbelt, sit back, relax, and enjoy the ride in this bench-to-bedside journey. I hope that youwill take as much pleasure in reading the volume as my distinguished colleagues and I have had inpreparing it.

Finally, I express my gratitude to the authors who took time to contribute to this book and, atCold Spring Harbor Laboratory Press, to Barbara Acosta and Richard Sever for their invaluableassistance and guidance during the preparation and production of the book.

SERGE PRZEDBORSKI

Columbia University

Preface

viii


The History of Parkinson’s Disease: Early ClinicalDescriptions and Neurological Therapies

Christopher G. Goetz

Department of Neurological Sciences and Department of Pharmacology, Rush UniversityMedical Center, Chicago, Illinois 60612

Correspondence: [email protected]

Although components of possible Parkinson’s disease can be found in very early docu-ments, the first clear medical description was written in 1817 by James Parkinson. In themid-1800s, Jean-Martin Charcot was particularly influential in refining and expandingthis early description and in disseminating information internationally about Parkinson’sdisease. He separated Parkinson’s disease from multiple sclerosis and other disorderscharacterized by tremor, and he recognized cases that later would likely be classifiedamong the Parkinsonism-plus syndromes. Early treatments of Parkinson’s disease werebased on empirical observation, and anticholinergic drugs were used as early as the nine-teenth century. The discovery of dopaminergic deficits in Parkinson’s disease and thesynthetic pathway of dopamine led to the first human trials of levodopa. Further historicallyimportant anatomical, biochemical, and physiological studies identified additionalpharmacological and neurosurgical targets for Parkinson’s disease and allow modern clini-cians to offer an array of therapies aimed at improving function in this still incurabledisease.

Important historical anchors for the study ofParkinson’s disease concern the early descrip-

tions of the disorder, its separation from otherneurological conditions, and the evolution oftherapy from empirical observations to rationaltreatment designs based on the growing knowl-edge of anatomy, biochemistry, and physiologyof the basal ganglia. Whereas the rest of thiscollection will focus on the contemporary andfuture directions of these issues, this articleprovides the background history of Parkinson’sdisease, highlighting persons and discoveriesprimarily from the nineteenth and early twenti-eth centuries.

EARLY CLINICAL DESCRIPTIONS

Defining Parkinson’s Disease

Parkinson’s disease was first medically describedas a neurological syndrome by James Parkinsonin 1817, though fragments of Parkinsonismcan be found in earlier descriptions (Parkinson1817). As examples, Sylvius de la Boe wroteof rest tremor, and Sauvages described festina-tion (Sylvius de la Boe 1680; Sauvages 1768;Tyler 1992). Much earlier, traditional Indiantexts from approximately 1000 BC and ancientChinese sources also provide descriptionsthat suggest Parkinson’s disease (Manyam 1990;

Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved

Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a008862

1


Zhang et al. 2006). In succinct and pithyEnglish, Parkinson captured the clinical picture:

Involuntary tremulous motion, with lessenedmuscular power, in parts not in action andeven when supported; with a propensity tobend the trunk forward, and to pass from a walk-ing to a running pace: the senses and intellectsbeing uninjured.

Parkinson reported on six case sketches, three ofthe patients observed in the streets of Londonand one only seen from a distance (Fig. 1).

Jean-Martin Charcot, in his teaching atthe Salpetriere over 50 years later, was morethorough in his descriptions and distinguishedbradykinesia as a separate cardinal feature of theillness (Charcot 1872):

Long before rigidity actually develops, patientshave significant difficulty performing ordinaryactivities: this problem relates to another cause.In some of the various patients I showed you,you can easily recognize how difficult it is forthem to do things even though rigidity or tremoris not the limiting feature. Instead, even a cursoryexam demonstrates that their problem relatesmore to slowness in execution of movementrather than to real weakness. In spite of tremor,a patient is still able to do most things, but heperforms them with remarkable slowness.Between the thought and the action there is aconsiderable time lapse. One would think neuralactivity can only be effected after remarkableeffort.

Charcot and his students described the clinicalspectrum of this disease, noting two proto-types, the tremorous and the rigid/akineticform. They described in full detail the arthriticchanges, dysautonomia, and pain that canaccompany Parkinson’s disease. Charcot wasalso the first to suggest the use of the term “Par-kinson’s disease” rejecting the earlier designa-tion of paralysis agitans or shaking palsy,because he recognized that Parkinson’s diseasepatients are not markedly weak and do not nec-essarily have tremor (Charcot 1872).

William Gowers, working in London, con-tributed an important study of Parkinson’sdisease demographics in his “Manual of Dis-eases of the Nervous System,” describing hispersonal experience with 80 patients in the1880s. He correctly identified the slight male

predominance of the disorder and studied thejoint deformities typical of the disease. Knownfor his descriptive prose, Gowers offered oneof the most memorable similes regarding Par-kinsonian tremor (Gowers 1888):

The movement of the fingers at the metacarpal-phalangeal joints is similar to that by whichOrientals beat their small drums.

Further clinical descriptions and studies of thepathologic changes related to Parkinson’s dis-ease were predominantly reported by the Frenchneurologic school. Richer and Meige (1895)provided clinical and morphologic details ofthe progressive stages of Parkinsonian disability,and the former provided drawings and statuesthat remain among the most important picto-rial documents related to Parkinson’s disease.Babinski commented on the strange motorfluctuations intrinsic to the disease itself (Ba-binski 1921). Brissaud first proposed damageto the substantia nigra as the anatomical seatof Parkinson’s disease, and Tretiakoff and Foixand Nicolesco pursued further pathologic stud-ies of the midbrain in relationship to the diseaseduring the 1920s (Tretiakoff 1921; Brissaud1925; Foix and Nicolesco 1925).

The most complete pathologic analysis ofParkinson’s disease and the clear delineationof the brain stem lesions was performed in1953 by Greenfield and Bosanquet (Greenfieldand Bosanquet 1953). The morbidity and clin-ical progression of Parkinson’s disease wasstudied in the important article by Hoehn andYahr in which their internationally recognizedstaging system was first introduced. This time-honored staging system is anchored in the dis-tinction between unilateral (Stage I) diseaseand bilateral disease (Stages II–V) and thedevelopment of postural reflex impairment(Stage III) as a key turning point in the disease’sclinical significance (Hoehn and Yahr 1967).

Separating Parkinson’s Disease fromOther Disorders

Prior to Charcot, the classification system, ornosology, of neurological disease was primitive,and disorders were largely grouped by primarysymptoms, for instance, tremors or weakness.

C.G. Goetz

2 Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a008862


Figure 1. Essay on the Shaking Palsy. James Parkinson’s short monograph is the first clear medical documentdealing with Parkinson’s disease (Parkinson 1817).

History of Parkinson’s Disease

Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a008862 3


Charcot’s first important contribution to thestudy of Parkinson’s disease was his differentia-tion of this disorder from other tremorous dis-orders, specifically multiple sclerosis (Charcot1872). Examining large numbers of patientswithin the vast Salpetriere Hospital in Paris,he developed a protocol to observe tremor atrest and then during action. He noted that thepatients with action tremor had accompanyingfeatures of weakness, spasticity, and visual dis-turbance. In contrast, those with rest tremor dif-fered in having rigidity, slowed movements, atypical hunched posture, and very soft speech.His early tremor studies were highly publicizedand helped to establish Parkinson’s disease as adistinct neurological entity that could be confi-dently diagnosed (Fig. 2).

Once the archetype of Parkinson’s diseasewas established, Charcot and his students iden-tified variants with features that were atypical

of classical Parkinson’s disease. These weretermed Parkinson’s disease without tremor,Parkinson’s disease with extended posture, andParkinson’s disease with hemiplegia. Thesecases are of historical interest, because they arelikely examples of disorders that would laterbe grouped under the term, Parkinsonism-plussyndromes, including progressive supranuclearpalsy, corticobasal degeneration, and multiplesystem atrophy. As one example, Charcot pre-sented a patient named Bachere on several occa-sions. On June 12, 1888, Charcot emphasizedthat Bachere did not have marked tremor, andin contrast to the usual arm flexion of typicalParkinson’s disease, he had a stiff and extendedposture.

Look how he stands. I present him in profile soyou can see the inclination of the head and trunk,well described by Parkinson. All this is typical.What is atypical, however, is that Bachere’s

Figure 2. Charcot and “myographic curves.” (Left) French neurologist Jean-Martin Charcot (1825–1893).(Right) Semi-diagrammatic “myographic curves” published by Charcot in 1887. The top tracing representsan intention tremor in multiple sclerosis. Segment AB indicates “at rest,” and BC indicates increasing oscillationsduring voluntary movement. The lower tracing represents a Parkinsonian tremor, with segment AB indicating atremor at rest, which persists in segment BC during voluntary movement. Charcot’s graphical recording methodon which these drawings were based is not described, but in other circumstances he relied on various pneumatictambour-like mechanisms (Charcot 1872; Goetz 1987).

C.G. Goetz



forearms and legs are extended, making theextremities like rigid bars, whereas in the ordi-nary case, the same body parts are partly flexed.One can say then that in the typical case ofParkinson’s disease, flexion is the predominantfeature, whereas here, extension predominatesand accounts for this unusual presentation. The

difference is even more evident when the patientswalk (Fig. 3) (Goetz 1987; Charcot 1888a).

In addition to extended posture, this patienthad particular facial bradykinesia and con-tracted forehead muscles. Charcot commentedthat the patient had the perpetual look of

Figure 3. Atypical Parkinsonism. (A) Drawing from Charcot’s original lesson, given on June 12, 1888, in whichhe contrasted a typical Parkinson’s disease showing a flexed posture (left) with a Parkinsonian variant thatincluded the absence of tremor and extended posture (right). Charcot regularly taught his students by compar-ing and contrasting cases of patients from the Salpetriere inpatient and outpatient services. (B) Four drawings byCharcot from his lesson on atypical Parkinson’s disease, dated June 12, 1888, showing the distinctive facial fea-tures of his patient, Bachere, showing forehead muscles and superior orbicularis in simultaneous contraction,activation of the palpebral portion of the orbicularis and combined activation of the frontalis superior portionof the orbicularis and platysma, giving a frightened expression in contrast to the placid, blank stare of typicalParkinson’s disease patients. This case is a compelling case of likely progressive supranuclear palsy (Goetz,1987; Charcot 1888a).




surprise, because the eyes remained widelyopened and the forehead continually wrinkled(Fig. 3) (Goetz 1987; Charcot 1888a). In amodern setting, Jankovic has detailed similarfacial morphology in Parkinsonism-plus patients,specifically those with progressive supranuclearpalsy (Jankovic 1984). No specific supranucleareye movement abnormalities were described.Another Salpetriere patient with “Parkinson’s dis-ease in extension” was described by Dutil in 1889and eye movement abnormalities are mentioned,although a supranuclear lesion is not docu-mented clinically (Dutil 1889; Goetz 1996). Thiscase also had highly asymmetric rigidity of theextremities, a feature more reminiscent of cortico-basal degeneration than progressive supranuclearpalsy. In this case, the extended neck posture wasgraphically emphasized:

The face is masked, the forehead wrinkled, theeyebrows raised, the eyes immobile. . . . Thisfacies, associated with the extended posture ofthe head and trunk, gives the patient a singularlymajestic air (Dutil 1889; Goetz 1996).

With clinical features reminiscent of both pro-gressive supranuclear palsy and corticobasaldegeneration, this patient was mentioned inseveral articles from the Salpetriere school, al-though no autopsy was apparently performed.Collectively, these cases show that even theearliest diagnosticians recognized classic Parkin-son’s disease and cases that needed to be distin-guished from it. Today, these Parkinsonism-plusdiagnoses are known to have additional distinc-tive features, including poor response to dopa-minergic therapies and different pathologicallesions than seen in Parkinson’s disease.

Another important entity to be distin-guished from Parkinson’s disease was posten-cephalitic Parkinsonism, today a rare cause ofParkinsonism, but a very frequent disorder inthe period after 1916. Following the influenzaepidemic of 1916–1917, a neurologic syndromethat included Parkinsonism, along with multi-ple other signs, occurred in alarming numbers(von Economo 1919). The additional behav-ioral, ocular, and motor problems of thesepatients attested to more diffuse neurologic dis-ease than seen typically in Parkinson’s disease.

This condition has largely disappeared in thetwenty-first century, because the survivorshave died and no recurrence of an epidemic ofthis magnitude has recurred. Other importantforms of atypical Parkinsonism to be distin-guished from Parkinson’s disease include ajuvenile form of Parkinson’s disease, originallydescribed by Willige in 1911 (Willige 1911),with a more full description and its associationwith atrophy of the globus pallidus provided byRamsey Hunt and van Bogaert (Ramsey Hunt1917; van Bogaert 1930).

In the years after these pioneering papers,the concepts of neural circuits evolved withkey nuclei of importance to the clinical presen-tation of Parkinsonism being the substantianigra, the globus pallidus, and the caudatenucleus and putamen (striatum). Involvementof the striatum resulting in Parkinsonism wasdocumented in a variety of neurological disor-ders. Striatal-nigral degeneration was describedby Adams, van Bogaert, and Vander Eecken,and, though originally classified as a single dis-ease, it has since been merged into the largerdiagnosis of multiple system atrophy (Adamset al. 1964). Parkinsonian states related to stria-tal pathology were later identified in the form ofHuntington’s disease, in which a Parkinsonianpresentation is referred to as the Westphal var-iant (Westphal 1883) and in cases of striatalcalcification, either on a hereditary basis (Bruynet al. 1964) or as an acquired metabolic disorderoften related to hypoparathyroidism (Muenterand Whisnant 1968).

The historical discussion of Parkinsoniandisorders that are frequently confused withParkinson”s disease includes drug-induced andtoxin-induced cases as well. The introductionof the antipsychotic agents, originally termedneuroleptics, led to dramatic improvements inschizophrenic and other psychotic behaviors,but induced Parkinsonism largely indistin-guishable from Parkinson’s disease itself (Steck1954). Later understanding that these drugsblock dopamine receptors in the striatumexplained this clinical presentation and led tothe development of antipsychotic drugs withlower proclivity to block striatal receptors andless propensity to induce Parkinsonism. The

C.G. Goetz



landmark observation on a cluster of youngpatients who presented with severe Parkinson-ism that appeared to be typical Parkinson’s dis-ease except for the young onset and severity ofsigns led to the discovery that the causativeagent was a self-administered narcotic deriva-tive, MPTP, that selectively damages the sub-stantia nigra (Langston et al. 1983). Thisproduct has provided a means to induce Parkin-sonism in experimental animals and remainsthe “gold standard” model to study Parkinson’sdisease in preclinical studies of new treatmentsfor Parkinson’s disease.

THE EVOLUTION OF TREATMENTS

The history of Parkinson’s disease is tightlylinked to therapeutic interventions, rangingfrom serendipitous observations to controlledclinical trials of specifically designed agents.

Parkinson devoted a chapter of his mono-graph to “considerations respecting the meansof cure” (Parkinson 1817). In humility and per-haps with a vision toward current concepts ofneuroprotection, he hoped for the identifica-tion of a treatment by which “the progress ofthe disease may be stopped” (Parkinson 1817).To this end, he advocated very early therapeuticintervention when signs were largely confinedto the arms without balance and gait impair-ments. Reflecting therapeutic approaches ofthe early nineteenth century, Parkinson rec-ommended venesection, specifically advocatingbloodletting from the neck, followed by vesica-tories to induce blistering and inflammation ofthe skin. Small pieces of cork were purposefullyinserted into the blisters to cause a “sufficientquantity” of purulent discharge (Parkinson1817). All these efforts were designed to divertblood and inflammatory pressure away fromthe brain and spinal cord, and in this way,decompress the medulla that Parkinson consid-ered the seat of neurological dysfunction.

Pharmacological Advances: Charcotand Gowers

Being the two most celebrated clinical neurol-ogists of the nineteenth century, Jean-MartinCharcot and William Gowers serve as important

icons for the study of standard and emergingtreatments for Parkinson’s disease. Charcot’sintern, Ordenstein, wrote his medical thesison the treatment of Parkinsonian tremor withbelladonna alkaloids, the first well-establishedtreatment of Parkinson’s disease (Ordenstein1972). These agents are centrally active anticho-linergic drugs that later would be understoodto affect the cholinergic/dopaminergic balancein the striatum and thereby improve Parkin-sonism. The credit of the observation of anti-cholinergic efficacy surely belongs to Charcothimself who managed his Salpetriere Schoolwith strict centralized supervision and oversawevery aspect of the neurological program. Aswith other young and aspiring students likeGilles de la Tourette and Pierre Marie, Orden-stein profited from publishing the observationwith his name as sole author, but contempora-ries would not have been deluded into thinkingof it as coming from anyone besides ProfessorCharcot. Of the many centrally active anticho-linergic agents of the era, Charcot’s preferredproduct for Parkinson’s disease was hyoscy-amine. This plant-based agent was prepared aspills, usually powder rolled into bits of whitebread, or as a syrup. As shown in a prescriptionlocated in the Philadelphia College of Physi-cians, Charcot’s anticholinergic treatment wassometimes combined with rye-based ergotproducts that in fact are the pharmacologicalbasis of some modern dopamine agonists,drugs that directly stimulate striatal dopaminereceptors and thereby simulate the activity ofdopamine itself (Fig. 4). Although Tyler hasaptly documented that Charcot was not thefirst interventionist to advocate hyoscyamine(Tyler 1992), Charcot’s name became linked tothe drug because of the widespread interna-tional publication of his lectures and classroomdemonstrations.

A unique historical opportunity to examinethe early treatment of Parkinson’s disease isprovided by a series of 18 unpublished lettersin the Charcot collection at the BibliothequeCharcot in Paris (Portfolio MAVIII: Parkinson’sdisease). These letters cover a period of at least15 months from January 1863 through March1864. Although the collection only contains




the patient’s letters and not Charcot’s replies,one can follow the doctor–patient interactionbecause of Charcot’s technique of closing hisletters traditionally with: “I would be mostobliged Monsieur, if you would remind me ofthis prescription the next time you write.” The

patient’s letters therefore systematically beginwith a summary of the prescribed therapy andfollow with the patient’s own observations. Inaddition to hyoscyamine and ergot-based prod-ucts, Charcot advocated an overall program ofrest and reduced stress. This type of therapy

Figure 4. Early treatment of Parkinson’s disease. Prescription dated 1877 from the College of Physicians ofPhiladelphia Library. In treating Parkinson’s disease, Charcot used belladonna alkaloids (agents with potentanticholinergic properties) as well as rye-based products that had ergot activity, a feature of some currently avail-able dopamine agonists. Charcot’s advice was empiric and preceded the recognition of the well-knowndopaminergic/cholinergic balance that is implicit to normal striatal neurochemical activity (Charcot 1872).

C.G. Goetz



was generally advocated for many primary neu-rological disorders (Mitchell 1908). For thispatient, he added camphor, silver nitrate, ironcompounds, henbane pills, and zinc oxide.The rationale for using these agents was notexplained by Charcot, and their pharmacologydoes not involve the dopamine system. Theuse of iron may have been based on Romberg’searlier observation that carbonate of iron inassociation with warm baths and cold affusionsto the head and back induced “a marked dimin-ution of symptoms.” (Romberg 1846). Whetherbased on his own experience or Romberg’swarning against trying strychnine, Charcotsteered away from this therapy for Parkinson’sdisease patients. Charcot was highly specific inhis instructions, insisting that quinquina, a qui-nine derivative, must be diluted with syrupmade from orange rind and each dose of silvernitrate must be impregnated in 9 g of soft breadto form an ingestible pill. The letters communi-cate encouragement to the patient, reinforce theneed for patience in facing chronic illness, and awillingness to consider new treatment strategiesif traditional ones were unsuccessful. However,his enthusiasm to try new interventions neverclouded his objective vision of efficacy. Inreviewing pharmacologic treatments for Par-kinson’s disease in 1872, Charcot stated:

Everything, or almost everything, has been triedagainst this disease. Among the medicinal sub-stances that have been extolled and which Ihave myself administered to no avail, I needonly enumerate a few (Charcot 1872).

In rejecting most medicines, Charcot advocatedvibratory therapy for the management of Par-kinson’s disease. Charcot had observed thatafter long carriage, train, or horseback rides,patients with Parkinson’s disease experiencedmarked symptom amelioration. He there-fore developed a replication device to providerhythmic movement by an electrically powered“shaking chair” (fauteuil trepidant) (Fig. 5)(Charcot 1892a). His student, Gilles de la Tou-rette, fashioned a helmet that was more easilytransported and vibrated the brain rather thanthe body (Goetz et al. 1995). Other used thera-pies included hydrotherapy, spa treatments,and light exercise. Electrical stimulation byfaradic, galvanic, or direct spark (frankliniza-tion) therapy was used to stimulate weakenedmuscles. Charcot was, however, adamant thatpatients with Parkinson’s disease were not par-ticularly weak, having tested them with dyna-mometers and finding their strength to benormal for most of the duration of illness. Itwas partly for this reason that he dismissedthe terms, paralysis agitans and shaking palsy,

Figure 5. Vibratory therapy. Charcot observed that patients with Parkinson’s disease experienced a reduction intheir rest tremor after taking a carriage ride or after horseback riding. He developed a therapeutic vibratory chairthat simulated the rhythmic shaking of a carriage (Goetz 1996). Avibratory helmet to shake the head and brainwas later developed. Such therapies were not used widely but the availability of modern medical vibratory chairsoffers an opportunity to confirm or refute Charcot’s observation.




and advocated instead the designation, Parkin-son’s disease.

A more unusual and hazardous early treat-ment of Parkinson’s disease involved the useof a suspension apparatus to stretch the spinalcord (Goetz et al. 1995). Developed in 1883 inRussia, the apparatus gained celebrity whenCharcot examined its safety and efficacy in avariety of disorders, including Parkinson’s dis-ease. Using gravity and the patient’s weight toput excessive vertical traction on the spinalcord and nerves, the therapist hoisted the sub-ject in mid-air with a pulley and a harness thatslipped under the chin and occiput. In Parkin-son’s disease patients, rigidity and some sensorysymptoms improved, but tremor was not ame-liorated. Edmond de Goncourt described thetherapy with allusions to the macabre artworkof Goya, and the serious side effects and stresson patients led Charcot to abandon this strategyshortly after its introduction in France (de Gon-court and de Goncourt 1887–1889).

Charcot’s British contemporary, WRGowers, followed similar treatment strategies.He stressed the negative effects of mental strainand physical exhaustion, advocating that “lifeshould be quiet and regular, freed, as far asmay be, from care and work.” (Gowers 1899).For tremor, he used hyoscyamine and also notedarsenic, morphia, conium (hemlock), and“Indian hemp” (cannabis) as effective agentsfor temporary tremor abatement. Writing spe-cifically of the power of cannabis and opiumin combination, he stated: “I have several timesseen a very distinct improvement for a consid-erable time under their use.” (Gowers 1899).Today, cannabis is known to have some dopami-nergic activation properties, but opium affectsthe motor system in a generalized, sedativemanner without direct or primary dopaminer-gic involvement.

Levodopa and Dopamine-Based Therapies

Through the mid-twentieth century, the treat-ment of Parkinson’s disease remained largelythat of the nineteenth century, and though awide variety of centrally active anticholinergicdrugs were developed and used, they all were

similar in their efficacy and side effect profiles.In the Handbook of Clinical Neurology, thechapter, “Drug treatment of parkinsonism andits assessment” (published in 1968) discussesten synthetic anticholinergic compounds anda potpourri of agents under the designation“Other drugs which have been recommended,some of them without any justification.” (Onu-aguluchi 1968). The emphasis of this periodremained on supportive physical therapy andthe management of hypersalivation, seborrhea,decubiti, and infections. In the context of thisrelative stagnation, the impact of levodopa wasmagnified.

As summarized by Hornykiewicz, dopa-mine was first synthesized in 1910 by G. Bargerand J. Ewens (Hornykiewicz 2002). In the sameyear, H. Dale discovered its weak sympathomi-metic qualities. These observations were laterremembered when P. Holtz discovered theenzyme, dopa decarboxylase and documentedthat levodopa was synthesized to dopaminethrough its action. At this time, dopamine wasrelegated to a simple intermediate compoundfor the synthesis of noradrenaline and adrena-line. The consistent identification of substan-tial amounts of dopamine in various tissues,however, prompted the search for a more pri-mary role. Working in Blaschko’s CambridgeUniversity laboratory, Hornykiewicz studiedblood pressure control in experimental animalsand clearly confirmed that dopamine haddistinct effects independent of other catechol-amines. Shortly thereafter, in the late 1950s,two seminal discoveries occurred: dopaminelocalization within the brain, specifically inthe striatum; and the development of thereserpine-model, later to be used as the firstmodel of Parkinsonism that was reversed by le-vodopa treatment. In concert, these discoveriesrapidly advanced hypotheses on the role of dop-amine loss in the pathogenesis of Parkinson’sdisease itself (Carlsson et al. 1958; Sano et al.1959), and led Bertler and Rosengred to con-clude that “dopamine is concerned with thefunction of the striatum and thus with the con-trol of movement.” (Bertler and Rosengred1959). Ehringer and Hornykiewicz turned tohuman brain and after examining a series of

C.G. Goetz



control specimens, discovered the striatal dopa-mine depletion in Parkinson’s disease and post-encephalitic parkinsonism brains (Ehringerand Hornykiewicz 1960). With the knowledgethat levodopa was the natural precursor todopamine, Hornykiewicz was now prepared tosuggest human trials in Parkinson’s diseasepatients.

Birkmayer received Hornykiewicz’s supplyof laboratory levodopa and injected it intrave-nously for the first time to Parkinsonianpatients in 1961. The antiakinetic effects werequickly published:

Bed-ridden patients who were unable to sit up,patients who could not stand up when seated,and patients who when standing could not startwalking performed all these activities with easeafter L-dopa [levodopa]. They walked aroundwith normal associated movements and theycould even run and jump. The voiceless, aphonicspeech, blurred by pallilalia and unclear articula-tion, became forceful and clear as in a normalperson (Birkmayer and Hornykiewicz 1961).

Subsequent open-label levodopa trials with oralpreparations confirmed both short and long-term benefits, and a double-blind placebo con-trolled trial followed (Barbeau 1969; Cotziaset al. 1969; Yahr et al. 1969). These reportslaunched levodopa’s establishment as the pre-mier agent to treat Parkinson’s disease symp-toms and signs. Although new formulationsand peripherally acting dopa-decarboxylaseinhibitors have added new dimensions to thetherapy, none of these events rival the firstdiscoveries.

Given that levodopa is a naturally occurringamino acid, researchers have reexamined oldertherapies to search for possible discoveriesof levodopa-containing compounds in earlymedicine. Of note, cowage or cowitch plant(Mucuna pruriens) is known under the nameof Atmagupta in Sanskrit and contains levo-dopa (Manyam 1990). One of the remediesused to treat the condition thought to be possi-ble Parkinson’s disease in traditional Indianmedicine is called Masabaldi Pacana, whichcontains beans of Mucuna pruriens. Theseobservations offer interesting, albeit indirect,evidence that patients with Parkinsonism may

have experienced the benefit of levodopa earlyin the history of medicine.

The more modern discoveries of dopamineagonists and enzyme inhibitors that enhancethe bioavailability of dopamine (monoamineoxidase inhibitors and catechol-O-methyltransferase inhibitors) date to the contempo-rary period and are of less importance to thishistorical review that emphasizes early discov-eries. These developments have been based onthe logical understanding of the dopaminesystem, metabolic pathways, and receptorpopulations. Further discoveries of modulat-ing influences by serotonin, adenosine, GABA,and glutamate systems have opened horizonsfor further pharmacological developments.The history of amantadine is of interest becauseof its serendipitous discovery as an anti-Par-kinsonian agent. Developed as an antiviralagent, it was used widely in nursing home pop-ulations, and Schwab noted its unexpectedbenefit on tremor, balance, and akinesia inboth Parkinson’s disease and postencephaliticparkinsonian patients (Schwab et al. 1969).This agent has mild dopamine effects, likelydue to inhibition of striatal synaptic dopaminereuptake so that more dopamine is left withinthe synapse to activate dopamine receptors. Ithas effects on the glutaminergic system withlikely indirect effects on dopamine functionthrough this mechanism.

SURGERY

In the early 1900s, surgery for movementdisorders was pioneered by V. Horsley and hisengineering colleague, R.H. Clarke (Fig. 6).They developed early stereotaxic equipmentto target brain nuclei, though their early sur-geries dealt with hyperkinetic disorders ratherthan Parkinson’s disease (Horsley and Clarke1908). Bucy and Case and Klemme excisedcerebral cortex to treat Parkinsonian tremor,but this type of ablative surgery inducedhemiparesis and was abandoned (Bucy andCase 1939; Klemme 1940). Meyers first focusedon the basal ganglia as a lesion target for abatingParkinsonian tremor in the 1940s and notedthat rigidity improved as well as tremor.




Importantly, spasticity and paresis did notcompromise the improvement (Meyers 1940).In 1953, by accident, I. Cooper cut the anteriorchoroidal artery during surgery on a Parkin-sonian patient and was forced to ligate it toprevent a hematoma. The unexpected andremarkable relief of tremor and rigidity onthe contralateral side led to more widespreaduse of this procedure, though mortality wasapproximately 10% (Cooper 1953). Electricalcoagulation procedures involving the globuspallidus, thalamus, and the ansa lenticularis(ansotomy) were performed with early stereo-taxic procedures (Spiegel and Wycis 1954).Hassler and Reichert focused more directly onthe ventrolateral nucleus of the thalamus, alsoreferred to as the Ventral Oralis Anterior (Voa)nucleus (Hassler 1955; Reichert 1962). All thesereports were hampered by the lack of involve-ment by medical neurologists with resultantconcerns of incomplete reporting, lack oflong-term follow-up and potential minimaliza-tion of morbidity. Further, the role of surgerywas eclipsed by the advent of levodopa in the1960s, so that a long hiatus occurred whensurgery was not extensively used in Parkinson’sdisease. During this time, however, moreadvanced surgical techniques were developed,and these innovations would be later appliedto Parkinson’s disease patients near the end of

the twentieth century. Such treatments date tothe contemporary period and include pallidot-omy, subthalamic nucleus ablation, deep brainstimulation to thalamus, pallidum and subtha-lamic, and various transplantation procedures.Most recent are the developments of gene-basedtherapies that have entered clinical trials.

Placebo Therapy

The relationships between dopamine releaseand positive motivation, novelty seeking behav-iors, and attention have allowed researchers tounderstand the long-acknowledged placeboimpact on Parkinson’s disease. The Charcot let-ters cited above suggest that Charcot too under-stood clearly the importance of his presenceand command over the patient’s well-being.As anchored as he remained in neuroanatomi-cal concepts through the end of his career, Char-cot’s last monograph was titled “Faith Cure”and dealt with the profound improvementsthat some patients with neurological diseaseexperienced through nontraditional therapies(Charcot 1892b). Placebo-controlled trials havebecome standard in Parkinson’s disease, evenin the surgical arena, mainly because a largepercentage of patients on placebo treatmentexperience objective improvement in parkin-sonism (Goetz et al. 2008). The facilitation of

Figure 6. Early surgical interventions. (Left) Victor Horsley (1857–1916) was a celebrated British surgeonwho attempted a surgical intervention on a movement disorder patient with athetosis in 1909. He excised motorcortex with substantial improvement in involuntary movements. (Middle) Working in London with hisphysiologist colleague, Robert Henry Clarke (1850–1926), he developed early stereotaxic equipment, first foranimal experiments and then for humans. (Right) This daunting surgical apparatus taken from their reportsin Brain in 1908 guided them to deep brain centers including the basal ganglia and the cerebellum (Horsleyand Clarke 1908).

C.G. Goetz



striatal dopaminergic activity in these settingshas been shown by neuroimaging techniques(de la Fuente-Fernandez et al. 2001). The fund-ing of federal grants for the specific study ofplacebo effects in Parkinson’s disease is, in itself,of historical significance (Goetz et al. 2008).

CONCLUDING REMARKS

Historical documents on Parkinson’s diseaseand descriptions that evoke Parkinsonismfrom eras prior to the first full medical delinea-tion of the disease provide a continuing sourceof potential neurological insights. As only oneexample, summarized in a review of traditionaland complementary therapies for Parkinson’sdisease (Manyam and Sanchez-Ramos 1999),in 1928, Lewin isolated an alkaloid from theBanisteriopsis caapi vine used in ceremonialmedicine among Amazonian tribes. He pro-vided purified banisterine to his colleague,Beringer, who tested it on patients with Parkin-son’s disease with reported marked benefit. Thedata were presented to the Berlin Medical As-sociation along with a film documenting thechanges in rigidity, bradykinesia, and gaitimpairment. Though this agent was not pur-sued further, the example underscores thepotential lessons from careful reading of tradi-tional medicine sources and the prospects fornew discoveries based on older observations.Charcot’s advocacy for vibratory therapy hasbeen tested in a modern setting (Kapur et al.2011), but Gowers’ encouraged use of Cannabishas yet to be systematically evaluated withstrong clinical trial methodology. Numerousother therapies have suggestive roles inParkinson’s disease but have not been rigorouslytested, including specific forms of physicalexercise, massage therapy, and relaxation tech-niques. The active participation of the Parkin-sonian subject in these treatments complicatesa controlled study design, but these interven-tions scientifically deserve to be tested withthe same rigor as new pharmacological or surgi-cal treatments. In the continuing search fortherapies to ameliorate current disability andto slow the natural deterioration that is implicitto Parkinson’s disease today, the guiding words

of Charcot remain modern and applicable: “Ifyou do not have a proven treatment for certainillnesses, bide your time, do what you can, butdo not harm your patients” (Charcot 1888b).

ACKNOWLEDGMENTS

Dr. Goetz acknowledges the Parkinson’s DiseaseFoundation that supports the Rush UniversityMedical Center Parkinson’s Disease and Move-ment Disorder Program with an annual grant.

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Index

AAADC. See Aromatic amino acid decarboxylase

AAV. See Adeno-associated virusAcetylcholine (ACh), functional imaging, 174–175ACh. See AcetylcholineAdaptive immune system

central nervous system, 381–382

cross-regulation with innate immunity in centralnervous system, 382–384

misfolded proteins in immune activation, 384–385Parkinson’s disease dysfunction, 385–388prospects for study, 391

therapeutic targeting, 388–391Adeno-associated virus (AAV)

gene therapy vectors, 129mouse models of Parkinson’s disease, 265

Aging

DNA polymerase-g studies in mutant mice, 218macroautophagy in protein quality control

effects, 336mitochondria aging hypothesis, 211–213, 305–306

Akinesia, motor control, 196–198a-Methyl-p-tyrosine, animal models of Parkinson’s

disease, 24a-Synuclein (SNCA)

aggregation potential, 69–70

autophagyautophagy response, 317–318, 337chaperone-mediated autophagy

degradation, 316inhibition by mutant forms, 316–317,

336–337mitophagy role, 318

autosomal dominant Parkinson’s disease clinicalfeatures, 24, 54–55

biomarkers, 77–78

function, 67–69gain-of-function and accumulation, 72–74gene dosage in Parkinson’s disease, 66knockdown therapy, 135–136

Lewy body. See Dementia with Lewy bodies;Lewy body

lipid interactions, 71–72loci. See PARK1; PARK4misfolded proteins in immune activation, 384–385

pathogenic effectscytoskeleton, 74–75

endoplasmic reticulum/Golgi apparatus, 76lysosome, 75mitochondria, 75

nucleus, 76proteasome, 75secretion and uptake, 77synapse, 74

posttranslational modifications, 70–71

protein–protein interactions, 71structure, 67–68synucleopathy models, 69therapeutic targeting, 77–78transgenic mouse, 266–267

ubiquitin proteasome system effects ofmutation, 331–332

AMPA receptor, neuronal phenotype of Parkinson’sdisease, 204

Amphetamines, animal models of Parkinson’s disease,248–249

Animal models. See a-Methyl-p-tyrosine;Amphetamines; Drosophila;6-Hydroxydopamine; Isoquinoline;

Lipopolysaccharide; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Mousemodels; Paraquat; Reserpine; Rotenone

Apoptosis. See Programmed cell deathAromatic amino acid decarboxylase (AADC), gene

therapy, 130–131ATP13A2, mutation

Parkinson’s disease, 57–58ubiquitin proteasome system dysfunction, 337–338

Autophagy

a-synucleinautophagy response, 317–318, 337chaperone-mediated autophagy

degradation, 316

inhibition by mutant forms, 316–317,336–337

mitophagy role, 318cytoplasmic cell death

overview, 355

paranatos, 355–356necroptosis, 356

DJ-1 role, 322functions, 315–316leucine-rich repeat kinase-2 role, 321–322

macroautophagy in protein quality control

399


Autophagy (Continued)aging effects, 336impairment in Parkinson’s disease, 336overview, 334–335

oxidative stress effects, 335–336mitophagy

parkin-dependent mitophagy, 320Parkinson’s disease, 319–320

molecular mechanisms, 315

organelle specificity, 314–315PINK1 function

isoforms, 321overview, 320–321protective function, 321

programmed cell deathdefects in Parkinson’s disease, 353–354mitophagy, 354–355overview, 353–354

prospects for study in Parkinson’s disease,322, 356–357

types, 313–314, 333–334Autosomal dominant Parkinson’s disease

clinical features, 24–25

gene mutations, 24–25, 54–55mouse models, 263pedigrees, 50, 52–53

Autosomal recessive Parkinson’s diseaseclinical features, 25–26

gene mutations, 25–26, 56–57mouse models, 264pedigrees, 50, 52–53

BBasal ganglia

function and motor symptoms, 198–199functional imaging at rest, 168functional organization

classic model, 152–154corticostriatal connections, 155

corticosubthalamic connections, 155–156domains, 154–155subcortical connections, 156

gross anatomy, 143–144nuclei

globus pallidus external segment, 150substantia nigra pars compacta, 151–152subthalamic nucleus, 150–151

pathophysiologydyskinesia, 157

parkinsonism, 156–157striatum

compartments, 146–147output nuclei

globus pallidus internal segment, 149substantia nigra pars reticulata, 149–150

projectionsafferents, 147–149efferents, 149neurons and interneurons, 144–145

Bcl-2 proteins, apoptosis mediation, 349–350b-Glucocerebrosidase (GBA)

a-synuclein accumulation effects, 75mutation and Parkinson’s disease risk, 58–59

Bioinformatics

biomarker discovery, 118–120overview, 115–116

Braak staging, Parkinson’s disease, 41Bradykinesia

motor control, 192–196

Parkinson’s disease, 18speed selection abnormalities, 186

CCalcium flux

L-type calcium channels

dopaminergic neuron susceptibility role inParkinson’s disease, 214–216

therapeutic targeting, 221–223metabolic burden on neurons, 205–207mitochondria in homeostasis, 207–208, 294,

301–303neuronal pacemaking and ionic homeostasis

challenge, 208–209neuron vulnerability in Parkinson’s disease

dopaminergic neurons, 213–220

nondopaminergic neurons, 220Caspase, activation in apoptosis, 348, 350CBD. See Corticobasal degenerationCDK5. See Cyclin-dependent kinase-5

Charcot, Jean-Martin, 2, 4–5, 7–10, 12, 17Chronic traumatic encephalopathy (CTE),

overview, 43Clarke, Robert Henry, 11–12Clinical presentation, Parkinson’s disease

autosomal dominant Parkinson’s disease, 24–25autosomal recessive Parkinson’s disease, 25–26exclusion criteria, 38historical perspective, 1–7motor symptoms

animal modelsassessment, 253–254MPTP monkey model, 233–234

bradykinesia, 18overview, 186–188

postural and gait impairment, 19rest tremor, 18–19rigidity, 19

nonmotor symptoms, 19–20

Corticobasal degeneration (CBD), overview, 43CTE. See Chronic traumatic encephalopathy

Index

400


Cyclin-dependent kinase-5 (CDK5), dysfunction inParkinson’s disease, 351–352

DDardarin. See Leucine-rich repeat kinase-2Default mode network (DMN), functional

imaging, 171–173Dementia with Lewy bodies (DLB)

differential diagnosis, 23parkinsonism etiology, 25

Diagnosis, Parkinson’s disease

clinical examination, 21criteria, 22differential diagnosis

dementia with Lewy bodies, 23

drug-induced parkinsonism, 22–23essential tremor, 23fragile X-tremor ataxia syndrome, 24multiple system atrophy, 23, 37–39progressive supranuclear palsy, 23–24, 37–39

vascular parkinsonism, 22historical perspective, 1–7imaging, 21–22incorrect diagnosis features, 21medical history, 20

DIP. See Drug-induced parkinsonismDJ-1

apoptosis protection, 347–348autophagy role, 322autosomal recessive Parkinson’s disease clinical

features, 26, 57, 100Drosophila studies of PINK1/Parkin pathway

modulation, 285evolution, 100–101

function, 104–106genetic testing, 59knockout mouse, 268–269locus. See PARK7mutation studies of parkinsonism development,

101–102prospects for study, 106

DLB. See Dementia with Lewy bodiesDMN. See Default mode networkDNA polymerase-g (POLG)

aging studies in mutant mice, 218mutation effects, 298

L-Dopa. See LevodopaDopamine

functional imaging, 165–166, 173–174

history of Parkinson’s disease treatment, 10–11striatum dopamine quantification in animal models

of Parkinson’s disease, 252Drosophila

advantages as Parkinson’s disease model system,277–278

gene identification in Parkinson’s disease, 276–277genetic and compound screening, 279knockdown studies, 279mutagenesis and loss-of-function studies, 278

overexpression studies, 278–279prospects for Parkinson’s disease studies, 285–286PTEN-induced putative kinase-1/Parkin

pathway studieslinks with other PARK loci, 284–285

mitochondrial fission promotion and fusioninhibition, 281–282

mitochondrial integrity, 279–281mitochondrial transport, 283–284mitophagy promotion, 282–283

site-specific transgenesis, 279Drug-induced parkinsonism (DIP)

differential diagnosis, 22–23drug types, 25

Dyskinesia. See specific dyskinesias

EEndoplasmic reticulum (ER)

a-synuclein mutant effects, 76

apoptosis response, 351protein quality control. See Autophagy; Ubiquitin

proteasome systemEpidemiology, Parkinson’s disease, 17–18ER. See Endoplasmic reticulum

Essential tremor (ET), differential diagnosis, 23ET. See Essential tremor

FFDDNP, protein aggregation imaging, 175–176FDOPA. See Positron emission tomography

fMRI. See Functional magnetic resonance imagingFragile X-tremor ataxia syndrome (FXTAS), differential

diagnosis, 24Functional magnetic resonance imaging (fMRI)

default mode network, 171–173principles, 165

FXTAS. See Fragile X-tremor ataxia syndrome

GGAD. See Glutamic acid decarboxylaseGaucher’s disease, parkinsonism risks, 337–338

GBA. See b-GlucocerebrosidaseGCH-1. See GTP cyclohydrolase-1GDNF. See Glial-derived neurotrophic factorGene therapy

enzyme replacementaromatic amino acid decarboxylase, 130–131glutamic acid decarboxylase, 132–133GTP cyclohydrolase-1, 130, 132tyrosine hydroxylase, 130, 132

Index

401


Gene therapy (Continued)glial-derived neurotrophic factor, 134–135principles, 127–128viral vectors

adeno-associated virus, 129lentivirus, 128

Genetics, Parkinson’s diseaseclassification by loci, 50–51genetic testing, 59

identification of new genes and riskfactors, 53–54

linkage analysis, 53–54loci. See specific locimonogenetic Parkinson’s disease, 54–58

pedigrees, 50, 52–53risk gene mutations in Parkinson’s

disease, 58–59Genomics, Parkinson’s disease

aberrant network activity identification, 116–118bioinformatics

biomarker discovery, 118–120overview, 115–116

historical perspective, 113–114

Mendelian versus complex disease, 112–113therapeutic application, 120–122

Glial-derived neurotrophic factor (GDNF)a-synuclein knockdown therapy, 135–136direct injection studies, 133–134

functional overview, 133gene therapy, 134–135parkin, 136–137prospects, 137–138

Globus pallidus

external segment, 150internal segment, 149

Glutamic acid decarboxylase (GAD), gene therapy,132–133

Gowers, William, 2, 7, 10GTP cyclohydrolase-1 (GCH-1),

gene therapy, 130, 132

HHistorical perspective, Parkinson’s disease

clinical descriptions, 1–3differential diagnosis, 2, 4–7genomics, 113–114treatment, 7–13

Horsley, Victor, 12HtrA2. See Omi/HtrA26-Hydroxydopamine (6-OHDA)

animal models of Parkinson’s disease, 244brain physiology, 243–244

structure, 242toxicity mechanisms, 246

Hypokinesia, motor control, 192–195

IInflammation

adaptive immune response. See Adaptive immunesystem

innate immune response. See Innate immune system

Innate immune systemcross-regulation with adaptive immunity in central

nervous system, 382–384inflammation in Parkinson’s disease

animal Parkinson’s disease model studieslipopolysaccharide, 376overview, 374toxin models, 374–375transgenic mouse studies, 375–376

epidemiological studies, 374microglia

activation in Parkinson’s disease, 372–374activators, 376characteristics and functions in brain,

370–372prospects for study, 377systemic inflammation impact on innate

immune cells, 372T cell activation, 374

misfolded proteins in immune activation, 384–385Isoquinoline, animal models of Parkinson’s disease,

249–250

JJellinger staging, multiple system atrophy, 42

KKnockout mouse. See Mouse models

LLentivirus, gene therapy vectors, 128

Leucine-rich repeat kinase-2 (LRRK2)autophagy role, 321–322autosomal dominant Parkinson’s disease clinical

features, 25, 55–56, 91–92discovery, 89–90

functionscytoskeleton, 93–94membrane trafficking, 92–93Parkinson’s disease protein pathway

overlap, 95

genetic testing, 59locus. See PARK8mutation

frequency, 90–91

functional effects, 94sites, 92

protein–protein interactions, 92

Index

402


structure, 92transgenic mouse, 267

Levodopa, history of Parkinson’s diseasetreatment, 10–11

Levodopa-induced dyskinesia (LID)functional imaging, 168–170MPTP monkey model, 235

Lewy body. See also a-Synuclein; Dementia withLewy bodies

characteristics, 39–40detection in animal models of Parkinson’s

disease, 252–253immunohistochemistry

multiple system atrophy, 35–36

Parkinson’s disease, 35–36, 67multiple system atrophy glial cytoplasmic

inclusions, 40, 66Lipopolysaccharide (LPS)

animal models of Parkinson’s disease, 250innate inflammation studies in Parkinson’s

disease models, 376LPS. See LipopolysaccharideLRRK2. See Leucine-rich repeat kinase-2

L-type calcium channel. See Calcium flux

MMacrophage. See MicrogliaMagnetic resonance imaging (MRI), Parkinson’s disease

diagnosis, 22Methamphetamine, animal models of Parkinson’s

disease, 248–249N-Methyl-D-aspartate receptor (NMDAR), neuronal

phenotype of Parkinson’s disease,204–205

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)

mitochondria effects, 296monkey models of Parkinson’s disease

anatomo-pathology, 232–233, 245

behavioral assessment, 235cognitive impairment, 234dyskinesia, 235Lewy body lack, 233limitations, 235–236

motor symptoms, 233–234sleep disturbances, 234–235species, 232

mouse models of Parkinson’s disease, 236–237species response in modeling Parkinson’s disease,

231, 245structure, 242toxicity mechanisms, 245ubiquitin proteasome system effects, 332

Microgliaactivation in Parkinson’s disease, 372–374, 387

activators in Parkinson’s disease, 376characteristics and functions in brain, 370–372

Mitochondriaaging hypothesis, 211–213, 305–306

a-synuclein function, 75, 318–319calcium homeostasis role, 207–208, 294,

301–303compartments, 293–294Drosophila studies of PINK1/Parkin pathway

links with other PARK loci, 284–285mitochondrial fission promotion and fusion

inhibition, 281–282mitochondrial integrity, 279–281mitochondrial transport, 283–284

mitophagy promotion, 282–283dynamics

fusion/fission, 298–300motility and regional distribution, 300–301

turnover, 301genetics, 297–298mitophagy. See Autophagyneuronal function, 209–210oxidative phosphorylation system

complex I blockade consequences, 296overview, 295

oxidative stress, 210–211Parkinson’s disease dysfunction overview, 306–307,

318–319

Parkin targets, 320programmed cell death

fragmentation, 352–353pathways, 303–305, 349

Monkey models. See 1-Methyl-4-phenyl-1,2,3,6-

tetrahydropyridineMotor control

akinesia, 196–198animal model assessment, 253–254

bradykinesia, 192–196hypokinesia, 192–195levels of description, 189–190motor symptom to motor control, 190–191overview, 188

rigidity, 190–192Mouse models, Parkinson’s disease

autosomal dominant Parkinson’s disease, 263autosomal recessive Parkinson’s disease, 264characterization, 266

knockout mouse modelsDJ-1, 268–269overview, 264–265parkin, 267–268PTEN-induced putative kinase-1, 268

MPTP, 236–237overview, 262prospects, 269–271transgenic mouse models

Index

403


Mouse models, Parkinson’s disease (Continued)a-synuclein, 266–267constructs, 262innate inflammation studies, 375–376

leucine-rich repeat kinase-2, 267test-off conditional models, 262, 264

virus-induced models, 265–266MPTP. See 1-Methyl-4-phenyl-1,2,3,6-

tetrahydropyridineMRI. See Magnetic resonance imagingMSA. See Multiple system atrophy

Multiple system atrophy (MSA)brain morphology, 34, 39clinical features, 38differential diagnosis, 23, 37–39glial cytoplasmic inclusions, 40

Jellinger staging, 42Lewy body immunohistochemistry, 35–36pathology comparison with Parkinson’s disease and

progressive supranuclear palsy, 40–41substantia nigra degeneration, 34–35

NNecroptosis, dysfunction in Parkinson’s disease, 356Neuronal phenotype, Parkinson’s disease

calcium channel, L-type targeting, 221–223metabolic burden

spiking, 205–208

synaptic transmission, 209mitochondria

aging hypothesis, 211–213oxidative stress, 210–211

overview, 204–205pacemaking and ionic homeostasis challenge,

208–209reconciliation with other pathogenesis models,

220–221

vulnerable neuronsdopaminergic neurons, 213–220non-dopaminergic neurons, 220

Niemann-Pick disease, parkinsonism risks, 337–338NMDAR. See N-Methyl-D-aspartate receptor

6-OHDA. See 6-Hydroxydopamine

OOmi/HtrA2

Drosophila studies of PINK1/Parkin pathwaymodulation, 284–285

function, 284

Oxidative stressa-synuclein role, 75–76macroautophagy effects, 335–336mitochondria

MPTP effects, 296

role, 210–211

Pp53, expression in Parkinson’s disease, 352p62, parkin-dependent mitophagy, 320Paranatos, dysfunction in Parkinson’s

disease, 355–356

Paraquatanimal models of Parkinson’s disease, 246–247structure, 242

PARK, autosomal dominant Parkinson’s disease clinical

features, 24PARK1. See also a-Synuclein

autosomal-dominant Parkinson’s disease clinicalfeatures, 24

PARK2. See also Parkin

autosomal recessive Parkinson’s disease clinicalfeatures, 25, 56–57

mutation and Parkinson’s diseasesusceptibility, 53

PARK4. See also a-Synuclein

autosomal-dominant Parkinson’s disease clinicalfeatures, 24

PARK5. See also Ubiquitin carboxy-terminalhydrolase-1

autosomal-dominant Parkinson’s disease clinical

features, 24–25PARK6. See also PTEN-induced putative kinase-1

autosomal recessive Parkinson’s disease clinicalfeatures, 26, 57

mutation and Parkinson’s disease susceptibility, 53

PARK7. See also DJ-1autosomal recessive Parkinson’s disease clinical

features, 26, 57PARK8. See also Leucine-rich repeat kinase-2

autosomal dominant Parkinson’s disease clinicalfeatures, 25, 55–56, 91–92

PARK9. See ATP13A2PARK13. See Omi/HtrA2Parkin

apoptosis protection, 348autosomal recessive Parkinson’s disease clinical

features, 25, 56–57, 100Drosophila studies of PINK1/Parkin pathway

links with other PARK loci, 284–285

mitochondrial fission promotion and fusioninhibition, 281–282

mitochondrial integrity, 279–281mitochondrial transport, 283–284mitophagy promotion, 282–283

evolution, 101function, 102–104gene therapy, 136–137genetic testing, 59

knockout mouse, 267–268locus. See PARK2mitochondrial targets, 320mitophagy role, 320, 354

Index

404


mutation studies of parkinsonism development,101–102

prospects for study, 106ubiquitin proteasome system effects of mutation,

331–332Parkinson, James, 1–3, 17Parkinson-dementia complex (PDC), overview, 43–44Parkinson’s disease-related cognitive pattern (PDCP),

functional imaging, 171–172

Parkinson’s disease-related pattern (PDRP), positronemission tomography, 166–168

Parkinson’s disease tremor-related pattern (PDTP),positron emission tomography, 168

PCD. See Programmed cell death

PDC. See Parkinson-dementia complexPDCP. See Parkinson’s disease-related cognitive patternPDRP. See Parkinson’s disease-related patternPDTP. See Parkinson’s disease tremor-related pattern

PET. See Positron emission tomographyPIB. See Pittsburgh Compound BPINK1. See PTEN-induced putative kinase-1Pittsburgh Compound B (PIB), protein aggregation

imaging, 175–176

Placebo therapy, historical perspective, 12–13POLG. See DNA polymerase-gPositron emission tomography (PET)

default mode network, 171functional imaging

dopaminergic dysfunction and motorsymptoms, 165–166

metabolic networks, 166–168levodopa-induced dyskinesia, 169–170neurotransmitter imaging, 173–175

Parkinson’s disease diagnosis, 21principles, 164–165protein aggregation imaging, 175–176resting metabolism studies, 171–172

Programmed cell death (PCD)apoptosis

animal models of Parkinson’s disease, 347–348assays, 346–347Bcl-2 proteins, 349–350

caspase activation, 348, 350cyclin-dependent kinase-5 dysfunction,

351–352endoplasmic reticulum response, 351p53 expression, 352

pathways, 348–349autophagy

defects in Parkinson’s disease, 353–354mitophagy, 354–355overview, 353–354

mitochondriafragmentation, 352–353pathways, 303–305, 349

overview, 345–346

Progressive supranuclear palsy (PSP)brain morphology, 34, 39clinical features, 38–39differential diagnosis, 23–24, 37–39

pathology comparison with Parkinson’s disease andmultiple system atrophy, 40–41

staging, 42–43substantia nigra degeneration, 34–35tau

immunohistochemistry, 35, 37pathology, 40

Proteasome. See Ubiquitin proteasome systemProtein quality control. See Autophagy; Ubiquitin

proteasome system

PSP. See Progressive supranuclear palsyPTEN-induced putative kinase-1 (PINK1)

apoptosis protection, 348autophagy function

isoforms, 321overview, 320–21, 354protective function, 321

autosomal recessive Parkinson’s disease clinicalfeatures, 26, 57, 100

Drosophila studies of PINK1/Parkin pathwaylinks with other PARK loci, 284–285mitochondrial fission promotion and fusion

inhibition, 281–282mitochondrial integrity, 279–281

mitochondrial transport, 283–284mitophagy promotion, 282–283

evolution, 101function, 102–104genetic testing, 59

knockout mouse, 268locus. See PARK6mutation studies of parkinsonism development,

101–102

prospects for study, 106

RReserpine, animal models of Parkinson’s disease, 248

Rest tremor, Parkinson’s disease, 18–19Rigidity

motor control, 190–192Parkinson’s disease, 19

Rotenone, animal models of Parkinson’s

disease, 247

SSingle-photon emission computed

tomography (SPECT)Parkinson’s disease diagnosis, 21

principles, 164–165protein aggregation imaging, 175–176

Index

405


Sleep disorders, Parkinson’s diseaseMPTP monkey model, 234–235overview, 20

SNc. See Substantia nigra pars compacta

SNCA. See a-SynucleinSPECT. See Single-photon emission computed

tomographySTN. See Subthalamic nucleusStriatum

basal ganglia projectionsafferents, 147–149corticostriatal connections, 155efferents, 149neurons and interneurons, 144–145

output nucleiglobus pallidus internal segment, 149substantia nigra pars reticulata,

149–150

compartments, 146–147dopamine quantification in animal models of

Parkinson’s disease, 252dopaminergic terminal quantification in

animal models of Parkinson’s

disease, 252Substantia nigra, degeneration in parkinsonian

disorders, 34–35Substantia nigra pars compacta (SNc)

dopaminergic neuron quantification in

animal models of Parkinson’sdisease, 251–252

neuron vulnerability in Parkinson’sdisease, 213–220

Substantia nigra pars reticulata, 149–152

Subthalamic nucleus (STN)corticosubthalamic connections, 155–156overview, 150–151

Surgical therapy, historical perspective, 11–12

TTau, progressive supranuclear palsy

immunohistochemistry, 35, 37pathology, 40

T cell

activation in Parkinson’s disease, 374, 387–388central nervous system, 382cross-regulation with innate immunity in central

nervous system, 383–384

regulatory T cell therapeutic targeting, 388–391TDP-43-related parkinsonism, overview, 44TH. See Tyrosine hydroxylaseTyrosine hydroxylase (TH), gene therapy, 130, 132

UUbiquitin carboxy-terminal hydrolase-1 (UCHL1)

locus. See PARK5Parkinson’s disease susceptibility gene, 58

Ubiquitin proteasome system (UPS)

ATP13A2 mutation and dysfunction, 337–338MPTP effects, 332overview, 329–331parkin mutation effects, 331–332protein misfolding versus clearance in Parkinson’s

disease, 328–329a-synuclein mutation effects, 331–332

UCHL1. See Ubiquitin carboxy-terminal hydrolase-1

VVascular parkinsonism, differential diagnosis, 22Ventral tegmental area (VTA), dopaminergic neuron

susceptibility in Parkinson’s disease,214, 216

Vibratory therapy, historical perspective, 9VTA. See Ventral tegmental area

Index

406


Documents

i-viii cshperspectmed-PKD-FM 1. · Drosophilaas a Model to Study Mitochondrial Dysfunction in Parkinson’s Disease, 275 Ming Guo Mitochondrial Biology and Parkinson’s Disease,