ShRNA targeting α-synuclein prevents neurodegeneration in a Parkinson's disease model

Alevtina D. Zharikov, Jason R. Cannon, Victor Tapias, Qing Bai, Max P. Horowitz, Vipul Shah, Amina El Ayadi, Teresa G. Hastings, J. Timothy Greenamyre, Edward A. Burton

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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-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.

Original languageEnglish (US)
Pages (from-to)2721-2735
Number of pages15
JournalJournal of Clinical Investigation
Volume125
Issue number7
DOIs
StatePublished - Jul 1 2015

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Synucleins
Parkinson Disease
Rotenone
Dopaminergic Neurons
Substantia Nigra
Small Interfering RNA
Corpus Striatum
Dependovirus
Environmental Exposure
Occupational Exposure
Dendrites

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zharikov, A. D., Cannon, J. R., Tapias, V., Bai, Q., Horowitz, M. P., Shah, V., ... Burton, E. A. (2015). ShRNA targeting α-synuclein prevents neurodegeneration in a Parkinson's disease model. Journal of Clinical Investigation, 125(7), 2721-2735. https://doi.org/10.1172/JCI64502

ShRNA targeting α-synuclein prevents neurodegeneration in a Parkinson's disease model. / Zharikov, Alevtina D.; Cannon, Jason R.; Tapias, Victor; Bai, Qing; Horowitz, Max P.; Shah, Vipul; El Ayadi, Amina; Hastings, Teresa G.; Greenamyre, J. Timothy; Burton, Edward A.

In: Journal of Clinical Investigation, Vol. 125, No. 7, 01.07.2015, p. 2721-2735.

Research output: Contribution to journalArticle

Zharikov, AD, Cannon, JR, Tapias, V, Bai, Q, Horowitz, MP, Shah, V, El Ayadi, A, Hastings, TG, Greenamyre, JT & Burton, EA 2015, 'ShRNA targeting α-synuclein prevents neurodegeneration in a Parkinson's disease model', Journal of Clinical Investigation, vol. 125, no. 7, pp. 2721-2735. https://doi.org/10.1172/JCI64502
Zharikov AD, Cannon JR, Tapias V, Bai Q, Horowitz MP, Shah V et al. ShRNA targeting α-synuclein prevents neurodegeneration in a Parkinson's disease model. Journal of Clinical Investigation. 2015 Jul 1;125(7):2721-2735. https://doi.org/10.1172/JCI64502
Zharikov, Alevtina D. ; Cannon, Jason R. ; Tapias, Victor ; Bai, Qing ; Horowitz, Max P. ; Shah, Vipul ; El Ayadi, Amina ; Hastings, Teresa G. ; Greenamyre, J. Timothy ; Burton, Edward A. / ShRNA targeting α-synuclein prevents neurodegeneration in a Parkinson's disease model. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 7. pp. 2721-2735.
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