title: shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson's disease model.
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.forename: Alevtina D
authors.initials: AD
authors.lastname: Zharikov
authors.forename: Jason R
authors.initials: JR
authors.lastname: Cannon
authors.forename: Victor
authors.initials: V
authors.lastname: Tapias
authors.forename: Qing
authors.initials: Q
authors.lastname: Bai
authors.forename: Max P
authors.initials: MP
authors.lastname: Horowitz
authors.forename: Vipul
authors.initials: V
authors.lastname: Shah
authors.forename: Amina
authors.initials: A
authors.lastname: El Ayadi
authors.forename: Teresa G
authors.initials: TG
authors.lastname: Hastings
authors.forename: J Timothy
authors.initials: JT
authors.lastname: Greenamyre
authors.forename: Edward A
authors.initials: EA
authors.lastname: Burton
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000473:pathology / Q000502:physiology; D055785:Gene Knockdown Techniques; D008297:Male; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D020734:Parkinsonian Disorders / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics* / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D055647:Rats, Transgenic; D012402:Rotenone / Q000633:toxicity; D013378:Substantia Nigra / Q000473:pathology / Q000503:physiopathology; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; C497606:Snca protein, rat; D051844:alpha-Synuclein; D012402:Rotenone