DOI 10.1212/WNL.0b013e31825dd3d0; Published online before print June 20, 2012;Neurology

Roger L. Albin and William T. Dauerpathogenesis?

Parkinson syndrome : Heterogeneity of etiology; heterogeneity of

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rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.Allsince 1951, it is now a weekly with 48 issues per year. Copyright © 2012 by AAN Enterprises, Inc.

® is the official journal of the American Academy of Neurology. Published continuouslyNeurology

Parkinson syndromeHeterogeneity of etiology; heterogeneity of pathogenesis?

Roger L. Albin, MDWilliam T. Dauer, MD

Neurology® 2012;79:202–203

Genetic discoveries over the past 15 years indicatethat distinct etiologic triggers can cause nigrostriataldegeneration. These discoveries indicate that Parkin-son disease (PD) is actually a syndrome (Parkinsonsyndrome [PS]), a cluster of signs and symptoms as-sociated with dysfunction of a specific organ or sys-tem. Differing etiologies can give rise to commonsyndromic features. Hepatic failure, for example, hasgenetic, toxic, and infectious causes. Similarly, thenigrostriatal degeneration associated with the defin-ing motor features of PS—resting tremor, bradykine-sia, and rigidity—can result from different geneticcauses. There are also hints of heterogeneity in spo-radic PS. Clinicians, for example, have long sus-pected that tremor-predominant PS has a morebenign course than PS dominated by postural insta-bility and gait disorder, the so-called PIGD variant.It is increasingly clear that several brain circuits de-generate in PS and there is evidence that subjectswith PS may differ in the degree of involvement ofnondopaminergic brain systems. For example, de-generation of corticopetal basal forebrain cholin-ergic projections is common in PS but imagingevidence from Shimada et al.1 shows relative spar-ing of this system in some subjects with longstand-ing sporadic PS.

The existence of different genetic etiologies for PSraises the question of whether there is a final com-mon pathway of neurodegeneration. There is limitedunderstanding of the functions of PS genes butmitochondrial dysfunction may be a commondownstream event.2 In this issue of Neurology®,Brockmann et al.3 present data suggesting heteroge-neity of pathogenetic mechanisms in the PS. Thisgroup used magnetic resonance spectroscopy imag-ing to assess markers of neuronal integrity, membranephospholipid metabolism, and energy metabolites. In agroup of subjects with PS with heterozygous glu-cocerebrosidase (GBA-PS) mutations, Brockmannet al. describe an interesting negative result—therewas no evidence of altered high-energy metabo-

lites. In a prior study of subjects with sporadic PS,this group applied the same methods and docu-mented definite changes in high-energy metabo-lites, a result consistent with a considerable bodyof previous work and consistent with mitochon-drial dysfunction in PS.4

The work of Brockmann et al. suggests thatGBA-PS is driven by a different pathogenetic mech-anism than other forms of the PS. GBA-PS is charac-terized by �-synuclein containing Lewy bodies,indicating a link between GBA dysfunction and�-synuclein accumulation. Mazzulli et al.5 presenteddata indicating that lysosomal dysfunction associatedwith GBA mutations results in stabilization of poten-tially neurotoxic oligomeric �-synuclein species. Thefailure to find bioenergetic abnormalities in thisgroup of subjects with GBA-PS suggests that mito-chondrial dysfunction is not universal in PS.

The results of Brockmann et al. require confirma-tion but are a warning that neurodegeneration in dif-ferent forms of PS may have different underlyingmechanisms. While the concept of mitochondrialdysfunction is well supported for some genetic formsof PS, it may not apply to other genetic forms of PSor some sporadic forms of PS.2,6 �-Synuclein deposi-tion is common to many forms of PS and toxic�-synuclein oligomeric species may mediate neuro-toxicity in some forms of PS. �-Synuclein toxicitycould result from primary abnormalities of proteinquality control, such as lysosomal defects in GBA-PD, or other abnormalities of autophagy or pro-teosomal function.5,6 Trials of disease-modifyingtherapies in PS to date have necessarily focused onenrolling large subject cohorts but have not paidmuch attention to possible PS subtypes. In thissetting, effects on subgroups would be easily over-looked. Looking ahead, defining PS subtypes andrefining clinical trial methods to allow evaluationof subtype-specific effects may be necessary tomake progress in developing disease-modifyingtherapies.

See page 213

Correspondence & reprintrequests to Dr. Albin:ralbin@umich.edu

From the Departments of Neurology (R.L.A., W.T.D.) and Cell and Developmental Biology (W.T.D.), University of Michigan, Ann Arbor; andGeriatrics Research, Education, and Clinical Center (R.L.A.), VAAAHS, Ann Arbor, MI.

Study funding: Supported by the Department of Veterans Affairs, NIH P01 NS015655.

Go to Neurology.org for full disclosures. Disclosures deemed relevant by the authors, if any, are provided at the end of this editorial.

EDITORIAL

202 Copyright © 2012 by AAN Enterprises, Inc.

Published Ahead of Print on June 20, 2012 as 10.1212/WNL.0b013e31825dd3d0

DISCLOSURER. Albin has received compensation for expert witness testimony in

litigation regarding dopamine agonist induced impulse control disor-

ders; receives grant support from the National Institutes of Health and

the Dept. of Veterans Affairs; served on the Data Safety and Monitor-

ing Boards for the QE3 and HORIZON trials; and serves on the

Scientific Advisory Board of the Hereditary Disease Foundation and

the Medical Advisory Board of the International Rett Syndrome Foun-

dation. W. Dauer is on the Scientific Advisory Boards of the Parkinson

Disease Foundation, Dystonia Medical Research Foundation and

Bachmann-Strauss Dystonia & Parkinson Foundation; and receives grant

support from the National Institutes of Health. Go to Neurology.org for

full disclosures.

REFERENCES1. Shimada H, Hirano S, Shinotoh H, et al. Mapping of

brain acetylcholinesterase alterations in Lewy body diseaseby PET. Neurology 2009;73:273–278.

2. Vives-Bauza C, Tocilescu M, Devries RL, Alessi DM,Jackson-Lewis V, Przedborski S. Control of mitochondrialintegrity in Parkinson’s disease. Prog Brain Res 2010;183:99–113.

3. Brockmann K, Hilker R, Pilatus U, et al. GBA-associatedPD: neurodegeneration, altered membrane metabolism,and lack of energy failure. Neurology 2012;79:213–220.

4. Hattingen E, Magerkurth J, Pilatus U, et al. Phosphorusand proton magnetic resonance spectroscopy demonstratesmitochondrial dysfunction in early and advanced Parkin-son’s disease. Brain 2009;132:3285–3297.

5. Mazzulli JR, Xu YH, Sun Y, et al. Alpha-synuclein inter-acts with Gaucher disease glucocerebrosidase and�-synuclein form a bidirectional pathogenic loop in. sy-nucleinopathies Cell 2011;146:37–52.

6. Corti O, Lesage S, Brice A. What genetics tells us aboutthe causes and mechanisms of Parkinson’s disease. PhysiolRev 2011;91:1161–1218.

Neurology 79 July 17, 2012 203

DOI 10.1212/WNL.0b013e31825dd3d0; Published online before print June 20, 2012;Neurology

Roger L. Albin and William T. DauerParkinson syndrome : Heterogeneity of etiology; heterogeneity of pathogenesis?

 June 24, 2012This information is current as of

 

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