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1.
Redox Biol ; 37: 101695, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32905883

RESUMEN

Convergent evidence implicates impaired mitochondrial function and α-Synuclein accumulation as critical upstream events in the pathogenesis of Parkinson's disease, but comparatively little is known about how these factors interact to provoke neurodegeneration. We previously showed that α-Synuclein knockdown protected rat substantia nigra dopaminergic neurons from systemic exposure to the mitochondrial complex I inhibitor rotenone. Here we show that motor abnormalities prior to neuronal loss in this model are associated with extensive α-Synuclein-dependent cellular thiol oxidation. In order to elucidate the underlying events in vivo we constructed novel transgenic zebrafish that co-express, in dopaminergic neurons: (i) human α-Synuclein at levels insufficient to provoke neurodegeneration or neurobehavioral abnormalities; and (ii) genetically-encoded ratiometric fluorescent biosensors to detect cytoplasmic peroxide flux and glutathione oxidation. Live intravital imaging of the intact zebrafish CNS at cellular resolution showed unequivocally that α-Synuclein amplified dynamic cytoplasmic peroxide flux in dopaminergic neurons following exposure to the mitochondrial complex I inhibitors MPP+ or rotenone. This effect was robust and clearly evident following either acute or prolonged exposure to each inhibitor. In addition, disturbance of the resting glutathione redox potential following exogenous hydrogen peroxide challenge was augmented by α-Synuclein. Together these data show that α-Synuclein is a critical determinant of the redox consequences of mitochondrial dysfunction in dopaminergic neurons. The findings are important because the mechanisms underlying α-Synuclein-dependent reactive oxygen species fluxes and antioxidant suppression might provide a pharmacological target in Parkinson's disease to prevent progression from mitochondrial dysfunction and oxidative stress to cell death.


Asunto(s)
Neuronas Dopaminérgicas , alfa-Sinucleína , Animales , Neuronas Dopaminérgicas/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo , Peróxidos/metabolismo , Ratas , Pez Cebra/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
2.
J Clin Invest ; 125(7): 2721-35, 2015 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-26075822

RESUMEN

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.


Asunto(s)
Degeneración Nerviosa/prevención & control , Trastornos Parkinsonianos/terapia , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/uso terapéutico , alfa-Sinucleína/antagonistas & inhibidores , alfa-Sinucleína/genética , Animales , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/patología , Neuronas Dopaminérgicas/fisiología , Técnicas de Silenciamiento del Gen , Masculino , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/fisiopatología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas Lew , Ratas Transgénicas , Rotenona/toxicidad , Sustancia Negra/patología , Sustancia Negra/fisiopatología , alfa-Sinucleína/fisiología
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