RT info:eu-repo/semantics/article
T1 shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model
A1 Zharikov, Alevtina D.
A1 Cannon, Jason R.
A1 Tapias Molina, Victor
A1 Bai, Qing
A1 Horowitz, Max P.
A1 Shah, Vipul
A1 El Ayadi, Amina
A1 Hastings, Teresa G.
A1 Greenamyre, J. Timothy
A1 Burton, Edward A.
AB 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.
SN 0021-9738
YR 2015
FD 2015
LK https://uvadoc.uva.es/handle/10324/63883
UL https://uvadoc.uva.es/handle/10324/63883
LA eng
NO Journal of Clinical Investigation, Julio 2015, vol. 125, n. 7. p. 2721-2735
NO Producción Científica
DS UVaDOC
RD 09-abr-2025