Glucocerebrosidase as a therapeutic target for Parkinson’s disease
| Autor: | Ellen Sidransky, Yu Chen, Jenny Do, Pankaj Sharma, Lu Chen, Richard Sam |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities Parkinson's disease Genetic enhancement Clinical Biochemistry Disease Article 03 medical and health sciences 0302 clinical medicine Lysosome Drug Discovery medicine Animals Humans Molecular Targeted Therapy Pharmacology Gaucher Disease business.industry Brain nutritional and metabolic diseases Parkinson Disease Genetic Therapy medicine.disease nervous system diseases 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Mutation Immunology alpha-Synuclein Glucosylceramidase Molecular Medicine α synuclein business Glucocerebrosidase |
| Zdroj: | Expert Opin Ther Targets |
| ISSN: | 1744-7631 1472-8222 |
| Popis: | INTRODUCTION: The association between Gaucher disease and Parkinson’s disease was first recognized in the clinic, where it was noted that patients with Gaucher disease, caused by the inherited deficiency of the lysosomal enzyme glucocerebrosidase, and their relatives with mutations in the glucocerebrosidase gene (GBA1) had a higher than expected incidence of Parkinson’s disease. Mutations in GBA1 are now accepted as the most commonly known genetic risk factor for Parkinson’s disease and dementia with Lewy bodies, and there appears to be an inverse relationship between glucocerebrosidase and α-synuclein, the key factor in Parkinson pathogenesis. The hypothesis that therapeutic enhancement of brain glucocerebrosidase levels might reduce the aggregation, accumulation or spread of α-synuclein has spurred great interest in glucocerebrosidase as a novel therapeutic target. AREA COVERED: This article explores the potential molecular mechanisms underlying the association between GBA1 mutations and Parkinson’s disease and outlines therapeutic strategies to increase brain glucocerebrosidase, including gene therapy, targeted delivery of recombinant glucocerebrosidase to the brain, small-molecule chaperones to rescue mutant glucocerebrosidase, and small-molecule modulators to activate wild-type glucocerebrosidase. EXPERT OPINION: Although an improved understanding of the mechanistic basis for GBA1-associated parkinsonism is still imperative, enzyme enhancement in the brain may have wide therapeutic implications. While gene therapy may ultimately be the more dramatic and effective approach, the development of less expensive and invasive small-molecule non-inhibitory chaperones or activators could significantly impact the disease course. |
| Databáze: | OpenAIRE |
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