期刊
HUMAN MOLECULAR GENETICS
卷 28, 期 11, 页码 1768-1781出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddz005
关键词
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资金
- Buchmann fellowship
- Israel Science Foundation [1300/13]
- Pfizer
- SHIRE
- NNE Research Program
Gaucher disease (GD) patients and carriers of GD mutations have a higher propensity to develop Parkinson's disease (PD) in comparison to the non-GD population. This implies that mutant GBA1 allele is a predisposing factor for the development of PD. One of the major characteristics of PD is the presence of oligomeric alpha-synuclein-positive inclusions known as Lewy bodies in the dopaminergic neurons localized to the substantia nigra pars compacta. In the present study we tested whether presence of human mutant GCase leads to accumulation and aggregation of alpha-synuclein in two models: in SHSY5Y neuroblastoma cells endogenously expressing alpha-synuclein and stably transfected with human GCase variants, and in Drosophila melanogaster co-expressing normal human alpha-synuclein and mutant human GCase. Our results showed that heterologous expression of mutant, but not WT, human GCase in SHSY5Y cells, led to a significant stabilization of alpha-synuclein and to its aggregation. In parallel, there was also a significant stabilization of mutant, but not WT, GCase. Co-expression of human alpha-synuclein and human mutant GCase in the dopaminergic cells of flies initiated alpha-synuclein aggregation, earlier death of these cells and significantly shorter life span, compared with flies expressing alpha-synuclein or mutant GCase alone. Taken together, our results strongly indicate that human mutant GCase contributes to accumulation and aggregation of alpha-synuclein. In the fly, this aggregation leads to development of more severe parkinsonian signs in comparison to flies expressing either mutant GCase or alpha-synuclein alone.
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