title: Exploring the link between glucocerebrosidase mutations and parkinsonism.
abstract: Clinical, genetic and pathological studies demonstrate that mutations in glucocerebrosidase (GBA), which encodes the lysosomal enzyme deficient in Gaucher disease (GD), are risk factors for Parkinson disease (PD) and related disorders. Some patients with GD and Gaucher carriers develop parkinsonism. Furthermore, subjects with PD have an increased frequency of GBA mutations. GBA-mutation carriers exhibit diverse parkinsonian phenotypes and have glucocerebrosidase-positive Lewy bodies. Although the mechanism for this association is unknown, we present several theories, including protein aggregation, prion transmission, lipid accumulation and impaired autophagy, mitophagy or trafficking. Each model has inherent limitations, and a second-hit mutation might be essential. Elucidation of the basis for this link will have important consequences for studying these diseases and should provide insights into lysosomal pathways and potential treatment strategies.
authors: Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Wendy
authors: W
authors: Westbroek
authors: Ann Marie
authors: AM
authors: Gustafson
authors: Ellen
authors: E
authors: Sidransky
mesh_terms: D001343:Autophagy / Q000235:genetics / Q000502:physiology; D060746:Endoplasmic Reticulum-Associated Degradation / Q000235:genetics; D005776:Gaucher Disease / Q000150:complications / Q000235:genetics*; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D020734:Parkinsonian Disorders / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D011328:Prions / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D011328:Prions; C497604:SNCA protein, human; D051844:alpha-Synuclein; D005962:Glucosylceramidase