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Neurodegener Dis. 2012;9(2):87-98. doi: 10.1159/000331328. Epub 2011 Oct 27.

Adaptive alternative splicing correlates with less environmental risk of parkinsonism.

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1
Department of Biological Chemistry, Life Sciences Institute, Hebrew University of Jerusalem, Jerusalem, Israel.

Abstract

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.

PMID:
22042332
DOI:
10.1159/000331328
[Indexed for MEDLINE]
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