The association between mutations in the lysosomal protein glucocerebrosidase and parkinsonism.
A body of work has emerged over the past decade demonstrating a relationship between mutations in glucocerebrosidase gene (GBA), the gene implicated in Gaucher disease (GD), and the development of parkinsonism. Several different lines of research support this relationship. First, patients with GD who are homozygous for mutations in GBA have a higher than expected propensity to develop Parkinson's disease (PD). Furthermore, carriers of GBA mutations, particularly family members of patients with GD, have displayed an increased rate of parkinsonism. Subsequently, investigators from centers around the world screened cohorts of patients with parkinsonism for GBA mutations and found that overall, subjects with PD, as well as other Lewy body disorders, have at least a fivefold increase in the number of carriers of GBA mutations as compared to age-matched controls. In addition, neuropathologic studies of subjects with parkinsonism carrying GBA mutations demonstrate Lewy bodies, depletion of neurons of the substantia nigra, and involvement of hippocampal layers CA2-4. Although the basis for this association has yet to be elucidated, evidence continues to support the role of GBA as a PD risk factor across different centers, synucleinopathies, and ethnicities. Further studies of the association between GD and parkinsonism will stimulate new insights into the pathophysiology of the two disorders and will prove crucial for both genetic counseling of patients and family members and the design of relevant therapeutic strategies for specific patients with parkinsonism.
Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI, National Institutes of Health, Bethesda, Maryland 20892-3708, USA.
John
J
DePaolo
Ozlem
O
Goker-Alpan
Ted
T
Samaddar
Grisel
G
Lopez
Ellen
E
Sidransky
D000328:Adult; D000368:Aged; D002648:Child; D004252:DNA Mutational Analysis; D056947:Enzyme Replacement Therapy; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005776:Gaucher Disease / Q000188:drug therapy / Q000453:epidemiology* / Q000235:genetics / Q000473:pathology; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease; D005962:Glucosylceramidase / Q000235:genetics* / Q000627:therapeutic use; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D020961:Lewy Body Disease / Q000453:epidemiology / Q000235:genetics; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020734:Parkinsonian Disorders / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D013378:Substantia Nigra / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
D051844:alpha-Synuclein; D005962:Glucosylceramidase