期刊
BRAIN
卷 137, 期 -, 页码 1304-1322出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awu002
关键词
glucocerebrosidase; alpha-synuclein; Gaucher disease; Parkinson's disease; lysosome
资金
- Intramural Research Programs of the National Human Genome Research Institute
- National Institutes of Health
- Brazilian Federal Agency for Support and Evaluation of Graduate Education CAPES
- Fulbright Brazil
Mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase, underlie Gaucher disease and are a risk factor for Parkinson's disease. Siebert et al. review emerging evidence that connects glucocerebrosidase with alpha-synuclein. Therapeutic strategies for Gaucher disease may inform the treatment of Parkinson's disease and other synucleinopathies.The lysosomal enzyme glucocerebrosidase, encoded by the glucocerebrosidase gene, is involved in the breakdown of glucocerebroside into glucose and ceramide. Lysosomal build-up of the substrate glucocerebroside occurs in cells of the reticulo-endothelial system in patients with Gaucher disease, a rare lysosomal storage disorder caused by the recessively inherited deficiency of glucocerebrosidase. Gaucher disease has a broad clinical phenotypic spectrum, divided into non-neuronopathic and neuronopathic forms. Like many monogenic diseases, the correlation between clinical manifestations and molecular genotype is not straightforward. There is now a well-established clinical association between mutations in the glucocerebrosidase gene and the development of more prevalent multifactorial disorders including Parkinson's disease and other synucleinopathies. In this review we discuss recent studies advancing our understanding of the cellular relationship between glucocerebrosidase and alpha-synuclein, the potential impact of established and emerging therapeutics for Gaucher disease for the treatment of the synucleinopathies, and the role of lysosomal pathways in the pathogenesis of these neurodegenerative disorders.
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