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- Title
shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson's disease model.
- Authors
Zharikov, Alevtina D.; Cannon, Jason R.; Tapias, Victor; Qing Bai; Horowitz, Max P.; Shah, Vipul; Ayadi, Amina El; Hastings, Teresa C.; Greenamyre, J. Timothy; Burton, Edward A.
- Abstract
Multiple convergent lines of evidence implicate both α-synuclein (encoded by SCNA) and mitochondrial dysfunction in the pathogenesis of sporadic Parkinson's disease (PD). Occupational exposure to the mitochondrial complex I inhibitor rotenone increases PD risk; rotenone-exposed rats show systemic mitochondrial defects but develop specific neuropathology, including α-synudein aggregation and degeneration of substantia nigra dopaminergic neurons. Here, we inhibited expression of endogenous α-synudein in the adult rat substantia nigra by adeno-associated virus-mediated delivery of a short hairpin RNA (shRNA) targeting the endogenous rat Snca transcript. Knockdown of α-synudein by -35% did not affect motor function or cause degeneration of nigral dopaminergic neurons in control rats. However, in rotenone-exposed rats, progressive motor deficits were substantially attenuated contralateral to α-synudein knockdown. Correspondingly, rotenone-induced degeneration of nigral dopaminergic neurons, their dendrites, and their striatal terminals was decreased ipsilateral to α-synudein knockdown. These data show that α-synudein knockdown is neuroprotective in the rotenone model of PD and indicate that endogenous α-synudein contributes to the specific vulnerability of dopaminergic neurons to systemic mitochondrial inhibition. Our findings are consistent with a model in which genetic variants influencing α-synudein expression modulate cellular susceptibility to environmental exposures in PD patients. shRNA targeting the SNCA transcript should be further evaluated as a possible neuroprotective therapy in PD.
- Subjects
ALPHA-synuclein; SUBSTANTIA nigra; ADENO-associated virus; ROTENONE; DOPAMINERGIC neurons; PARKINSON'S disease; LABORATORY rats; ANIMAL models in research
- Publication
Journal of Clinical Investigation, 2015, Vol 125, Issue 7, p2721
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI64502