期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 175, 期 -, 页码 42-55出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2021.08.230
关键词
Glucocerebrosidase; Alpha-synuclein; Parkinson disease; Gaucher disease; Synucleinopathies; Dementia with lewy bodies; Neurodegeneration; Autosomal recessive; Ambroxol
资金
- JPND [MR/T046007/1]
- Cure Parkinson Trust
- Parkinson UK
- Michael J Fox Foundation ASAP initiative
- NIHR UCLH BRC
Research has shown that mutations in the GBA gene can lead to Gaucher disease and Parkinson's disease, as well as increase the risk of neurodegeneration in heterozygous carriers. Despite proposing several potential pathogenic pathways, the understanding of how GBA mutations predispose to neurodegeneration remains incomplete.
Biallelic (homozygous or compound heterozygous) glucocerebrosidase gene (GBA) mutations cause Gaucher disease, whereas heterozygous mutations are numerically the most important genetic risk factor for Parkinson disease (PD) and are associated with the development of other synucleinopathies, notably Dementia with Lewy Bodies. This phenomenon is not limited to GBA, with converging evidence highlighting further examples of autosomal recessive disease genes increasing neurodegeneration risk in heterozygous mutation carriers. Nevertheless, despite extensive research, the cellular mechanisms by which mutations in GBA, encoding lysosomal enzyme beta-glucocerebrosidase (GCase), predispose to neurodegeneration remain incompletely understood. Alpha-synuclein (A-SYN) accumulation, autophagic lysosomal dysfunction, mitochondrial abnormalities, ER stress and neuroinflammation have been proposed as candidate pathogenic pathways in GBA-linked PD. The observation of GCase and A-SYN interactions in PD initiated the development and evaluation of GCase-targeted therapeutics in PD clinical trials.
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