DisordersResulting from Defects in Lysosomal Function

The function of Lysosomes

� Lysosomes are involved in three major cell functions:

� 1).phagocytosis� 2).autophagy� 3).endocytosis� 3).endocytosisLysosomes are an animal cell′s digestive

organelles ,their total enzymes can hydrolyze virtually every type of biological macromolecule.

LSD Sub-Categories

LSD Sub-Categories

� Every LSD results from a problem with the lysosomal process by which enzymes rid cells of substrate.

� Lysosomes contain about 40 different � Lysosomes contain about 40 different hydrolytic enzymes, produced in cell cytoplasm and each responsible for breaking down a particular substrate.

LSD Sub-Categories

� When a lysosomal enzyme (or another protein that directs it) is deficient or malfunctioning, the substrate it targets accumulates, interfering with normal cellular activity.

Healthy cell vs. LSD cell with accumulated substrat e

LSD Sub-Categories

� Sub-categories are based on the type of enzymatic defect and/or stored substrate product.

� For example, the mucopolysaccharidoses � For example, the mucopolysaccharidoses (MPS) are grouped together because each results from an enzyme deficiency that causes accumulation of particular glycosaminoglycan (GAG) substrates.

and diseases that fall under them

MPS I (Hurler, Hurler-Scheie, Scheie)

MPS II (Hunter)

MPS III (San filipo Types A,B,C and D)

I - Defective metabolism of glycosaminoglycans " the mucopolysaccharidoses"

MPS IV (Morquio type A and B)

MPS VI (Maroteaux-Lamy)

MPS VII (Sly)

MPS IX (Hyaluronidase deficiency)

Multiple Sulfatase deficiency

Aspartylglucosaminuria

Fucosidosis, type I and II

Mannosidosis

II - Defective degradation of glycan portion of glycoproteins

Mannosidosis

Sialidosis, type I and II

III - Defective degradation of glycogen

Pompe disease

Acid sphingomyelinase deficiency (Niemann-Pick A & B)

Fabry disease

Farber disease

Gaucher disease, type I, II and III

GM1 gangliosidosis, type I, II and III

IV - Defective degradation of sphingolipid components

GM1 gangliosidosis, type I, II and III

GM2 gangliosidosis (Tay-Sachs type I, II, III and S andhoff

Krabbe disease

Metachromatic leukodystrophy, type I, II and III

V - Defective degradation of polypeptides

Pycnodysostosis

VI - Defective degradation or transport of VI - Defective degradation or transport of cholesterol, cholesterol esters, or other complex lipids

Neuronal ceroid lipofuscinosis, type I, II, III and IV

VII - Multiple deficiencies of lysosomal enzymes

Galactosialidosis

Mucolipidosis, type II and III

VIII - Transport and trafficking defects CystinosisCystinosis

Danon disease

Mucolipidosis type IV

Niemann-Pick type C

Infantile sialic acid storage disease

Salla disease

Biochemical and Cellular basis of lysosomal storage disorders

Biochemical and Cellular basis of lysosomal storage disorders

1. Most mutations result in the delivery of a defectiv e enzyme with a reduced catalytic activity to lysosome s

2. Another (activator) protein required for optimal hydrolase activity is defective or absent

3. A mutation that causes misfolding results in defect ive transport of a lysosomal hydrolase out of the endoplasmic reticulum

4. Alternatively, defective transport of a lysosomal hydrolase out of the ER occurs because a multi-enzyme complex that is required for transport cannot form (Cathepsin A / sialidase / ββββ-galactosidase )

Biochemical and Cellular basis of LSDs…

5 In the Golgi, defective glycosylation could result in an enzyme with reduced catalytic activity

6 Alternatively, defective glycosylation with mannose -6-phosphate in the Golgi could produce an enzyme that cannot reach lysosomes

Defects in other transport steps from the Golgi 7 Defects in other transport steps from the Golgi could also lead to an LSD

8 Defects in integral lysosomal membrane proteins with transporter roles

9 Defects in proteins that are involved in other vit al regulatory events of lysosomal function (LAMP2, lysosomal associated membrane protein 2)

Biochemical and Cellular basis of LSDs

Futerman AH & van Meer G (Futerman AH & van Meer G (20042004) ) 55::554554--565565

1 1 catalytic activitycatalytic activity

2 2 activatoractivator

3 3 misfoldingmisfolding

4 4 multienzyme complexmultienzyme complex

5 5 glycosylationglycosylation

6 6 MM--66--P targettingP targetting

7 7 other transport stepsother transport steps

8 8 membrane transportersmembrane transporters

9 9 membrane regulatorsmembrane regulators

Diseases resulting from defects in lysosomal function

� I-cell disease� Lysosomal storage diseases

I-cell disease� Caused by the deficiency of an enzyme(N-

acetyglucosamine phosphotransferase。Because of the absence of this enzyme,the secreted enzymes lack the mannose phosphate residues which is a signal for targeting lysosomal enzymes to lysosomes.

� Symptoms:a rare inherited metabolic disorder characterized by coarse facial features,skeletal abnormalities and mental retardation .Many cells from these patients contain lysosomes that are bloated with undegraded materials.

Lysosomal storage diseases

� Characterized by the deficiency of a single lysosomal enzyme and corresponding accumulation of undegraded substance,for example these diseases resulting from an acumulation of undegraded sphingolipids.acumulation of undegraded sphingolipids.

� Pompe disease is also a type of Lysosomal storage diseases.

� Pompe disease, a hereditary metabolic disorder , result from the absence of a lysosomal enzyme, α-glucosidase whose absence will result in undigested glycogen accumulated in lysosomes.

� Symptoms:accumulation of glycogen in all organs,cardiorespiratory failure and death , usually before age 2. usually before age 2.

Tay-Sachs diseaseGeneral situation:The best-studied lysosomal storage diseasesIncidence: very rare in the general population 1 in 3600 newborns among Jews of eastern 1 in 3600 newborns among Jews of eastern

European ancestryHas dropped dramatically in this ethnic

population in recent years

Tay-Sachs disease

Cause:

Deficiency of the enzyme β-N-hexosaminidase A hexosaminidase A the ganglioside Gm2 accumulate in the bloated lysosomal of brain cellsdysfunction

Tay-Sachs disease

Tay-Sachs diseaseCharacterized:Progressive mental and motor retardation

Symptom:Symptom:Skeletal ,cardiac ,and abnormalities

Tay-Sachs disease

Preventive:

Identification of carriers

Genetic counseling of parents at risk

Prenatal diagnosis by amniocentesis

Other cellular defects:

Niemann-Pick disease:

occurrence: A, B collectively- 1/1000 Ashkenazim Jews are carriers, type C no ethnic distributiontype A accounts for 85% of cases

Symptoms: enlarged spleen and liver, enlarged lymph nodes, darkening of skin, neurologic impairment (not in B), cherry red spot

genetic defect: A and B, mutant for sphingomyelinaseType C mutants: two loci, two proteins, multi-transmembrane protein (related toType C mutants: two loci, two proteins, multi-transmembrane protein (related tohedgehog receptor ‘patched’ and small co-protein(cholesterol binding protein/carrier?). Homolog NPCL1 involved in cholesterol absorption in gut.

storage material: sphingomyelin, cholesterol and sphingolipids

Diagnosis: ‘filipin’ staining

cell biology (and diagnosis): mislocalised unesterified cholesterol, neurofibrillary tangles

Endosomal trafficking jam? cholesterol and sphingolipids required to organise endosomaltrafficking steps. Cholesterol recycled from lysosome.

Batten disease

A family of closely related disorders9 forms: congenital, infantile, late infantile, juvenileAdult

occurrence: most common childhood neurodegeneration 1/8000 livebirths

Symptoms: visual defects, seizures, stumbling, echolalia, eventual loss of sight speech and motor skills, early death after blindness, dementia.

storage material: Lipofuscin/ceroid, subunit C of mitochondrial ATP synthasestorage material: Lipofuscin/ceroid, subunit C of mitochondrial ATP synthase

Prognosis and treatment: anti-convulsives, therapy. Death in childhood

lysosomal storage disease

Gaucher’s diseaseDeficiency of B-glucosidase in leukocyte and

fibroblast.Low level of Factor IXHigh level of acid phosphatseHigh level of acid phosphatseAccumulate large quantities of

glucocerebroside lipids in the lysosomes of macrophagesSpleen enlargement and anemia

Treatment of lysosomal storage diseasesGaucher’s disease

Accumulate large quantities of glucocerebroside lipids in the lysosomes of macrophagesSpleen enlargement and anemiaSpleen enlargement and anemia

Attempt Enzyme replacement therapy—alleviateInfusing a solution of the normal human enzyme into the bloodstream—the enzyme was taken up by liver cells—unsuccessful

Treatment of lysosomal storage diseasesEffective treatment:

Purify the enzyme from human placental tissue treated with 3 different glycosidases to remove terminal sugars on the enzyme’s oligosaccharide chains expose mannose residues chains expose mannose residues infusion into the bloodstream recognized by mannose receptor on the surface of macrophages taken up by endocytosis delivered to the natural target site in the cell where the deficiently is manifested

Treatment of lysosomal storage diseasesClinical trials :

Enzyme replacement therapy

Genetic therapy

Marrow replanting therapy