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

J Clin Invest. 2015 Jul 1;125(7):2721-35. doi: 10.1172/JCI64502. Epub 2015 Jun 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Dopaminergic Neurons / pathology
  • Dopaminergic Neurons / physiology
  • Gene Knockdown Techniques
  • Male
  • Nerve Degeneration / pathology
  • Nerve Degeneration / physiopathology
  • Nerve Degeneration / prevention & control*
  • Parkinsonian Disorders / pathology
  • Parkinsonian Disorders / physiopathology
  • Parkinsonian Disorders / therapy*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics*
  • RNA, Small Interfering / therapeutic use*
  • Rats
  • Rats, Inbred Lew
  • Rats, Transgenic
  • Rotenone / toxicity
  • Substantia Nigra / pathology
  • Substantia Nigra / physiopathology
  • alpha-Synuclein / antagonists & inhibitors*
  • alpha-Synuclein / genetics*
  • alpha-Synuclein / physiology


  • RNA, Messenger
  • RNA, Small Interfering
  • Snca protein, rat
  • alpha-Synuclein
  • Rotenone