Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 7, Pages 2721-2735Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI64502
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Funding
- NIA NIH HHS [P30 AG024827] Funding Source: Medline
- NIEHS NIH HHS [RC1 ES018058, ES022644, R00 ES019879, R01 ES020327, ES020718, R01 ES020718, K99 ES019879, R01 ES022644, ES019879, ES018058, ES020327] Funding Source: Medline
- NINDS NIH HHS [NS059806, P01 NS059806] Funding Source: Medline
- BLRD VA [I01 BX000548] Funding Source: Medline
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Multiple convergent lines of evidence implicate both alpha-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 alpha-synuclein aggregation and degeneration of substantia nigra dopaminergic neurons. Here, we inhibited expression of endogenous alpha-synuclein 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 alpha-synuclein by similar to 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 alpha-synuclein knockdown. Correspondingly, rotenone-induced degeneration of nigral dopaminergic neurons, their dendrites, and their striatel terminals was decreased ipsilateral to alpha-synuclein knockdown. These data show that alpha-synuclein knockdown is neuroprotective in the rotenone model of PD and indicate that endogenous alpha-synuclein contributes to the specific vulnerability of dopaminergic neurons to systemic mitochondrial inhibition. Our findings are consistent with a model in which genetic variants influencing alpha-synuclein 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.
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