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shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model
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shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model
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Journal Article
shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model
2015
Overview
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-synuclein aggregation and degeneration of substantia nigra dopaminergic neurons. Here, we inhibited expression of endogenous α-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 α-synuclein 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-synuclein knockdown. Correspondingly, rotenone-induced degeneration of nigral dopaminergic neurons, their dendrites, and their striatal terminals was decreased ipsilateral to α-synuclein knockdown. These data show that α-synuclein knockdown is neuroprotective in the rotenone model of PD and indicate that endogenous α-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 α-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.
Publisher
American Society for Clinical Investigation
Subject
alpha-Synuclein - antagonists & inhibitors
/ alpha-Synuclein - physiology
/ Animals
/ Dopaminergic Neurons - pathology
/ Dopaminergic Neurons - physiology
/ Male
/ Nerve Degeneration - pathology
/ Nerve Degeneration - physiopathology
/ Nerve Degeneration - prevention & control
/ Parkinsonian Disorders - pathology
/ Parkinsonian Disorders - physiopathology
/ Parkinsonian Disorders - therapy
/ Rats
/ RNA, Small Interfering - genetics
/ RNA, Small Interfering - therapeutic use
