期刊
NEURODEGENERATIVE DISEASES
卷 9, 期 2, 页码 87-98出版社
KARGER
DOI: 10.1159/000331328
关键词
Acetylcholinesterase; Alternative splicing; Animal models; Brain; Parkinson's disease
资金
- European Community's Network of Excellence [LSH-2004-1.1.5-3]
- ISF-MORASHA [399/07]
- Rosetrees Foundation
- Hebrew University
- Edmond and Lily Safra Center for Brain Sciences (ELSC)
- Gatsby Foundation
- Israel Academy of Sciences and Humanities
Background/Objective: Environmental exposure to anti-acetylcholinesterases (AChEs) aggravates the risk of Parkinsonism due to currently unclear mechanism(s). We explored the possibility that the brain's capacity to induce a widespread adaptive alternative splicing response to such exposure may be involved. Methods: Following exposure to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), brain region transcriptome profiles were tested. Results: Changes in transcript profiles, alternative splicing patterns and splicing-related gene categories were identified. Engineered mice over-expressing the protective AChE-R splice variant showed less total changes but more splicing-related ones than hypersensitive AChE-S over-expressors with similarly increased hydrolytic activities. Following MPTP exposure, the substantia nigra and prefrontal cortex (PFC) of both strains showed a nuclear increase in the splicing factor ASF/SF2 protein. Furthermore, intravenous injection with highly purified recombinant human AChE-R changed transcript profiles in the striatum. Conclusions: Our findings are compatible with the working hypothesis that inherited or acquired alternative splicing deficits may promote parkinsonism, and we propose adaptive alternative splicing as a strategy for attenuating its progression. Copyright (C) 2011 S. Karger AG, Basel
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