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shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model
Alevtina D. Zharikov, … , J. Timothy Greenamyre, Edward A. Burton
Alevtina D. Zharikov, … , J. Timothy Greenamyre, Edward A. Burton
Published June 15, 2015
Citation Information: J Clin Invest. 2015;125(7):2721-2735. https://doi.org/10.1172/JCI64502.
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Research Article Neuroscience Article has an altmetric score of 58

shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model

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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.

Authors

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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Figure 4

Absence of motor deficit following nigral α-synuclein knockdown.

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Absence of motor deficit following nigral α-synuclein knockdown.
Animals...
Animals from cohort 2 (unilateral AAV-sh[SNCA] or AAV-sh[control] into the substantia nigra) were analyzed for phenotypes attributable to α-synuclein knockdown. (A) The rats’ weights were measured 7 days prior to stereotactic vector inoculation and then daily for 42 days thereafter. Data points show mean ± SEM. (B) A postural instability test was used to evaluate forelimb motor function. For each forelimb, the displacement of the rat necessary to provoke a compensatory forelimb movement was measured (see Methods). The ratio of this distance between the left and right forelimbs was determined at each time point shown. Data points show mean ± SEM for the AAV-sh[control] (gray circles) and AAV-sh[SNCA] (black squares) groups; the line shows ratio = 1 that would indicate perfectly symmetric motor function. Pre, before surgery. (C and D) Spontaneous exploratory behavior in a transparent cylinder was evaluated as a second test for forelimb motor function. (C) Rearing movements resulting in a unilateral forelimb contact with the cylinder wall were counted in each 5-minute time period. (D) The number of wall contacts made by the left forepaw was calculated as a percentage of the total unilateral forepaw contacts. Data points show mean ± SEM for the AAV-sh[control] (gray circles) and AAV-sh[SNCA] (black squares) groups. The line in D shows a value of 50% that would indicate perfectly symmetric motor function.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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