A model of nitric oxide induced α-synuclein misfolding in Parkinson's disease

Inducible nitric oxide synthase (iNOS) upregulation and consequent NO formation are well-recognized neuroinflammatory responses associated with Parkinson's disease (PD). These contribute to nitrosative protein modifications affecting neuronal injury and cell death. Indeed, a pathobiologic signature for PD is Lewy body formation containing misfolded and aggregated forms of alpha-synuclein (α-syn). Moreover, nitration of α-syn promotes protein aggregation in disease. To model such pathological events, we constructed controllable iNOS and bicistronic α-syn-IRES-tTA adeno-associated virus (AAV) expression vectors. Transduction of iNOS and α-syn AAV constructs led to nitration of α-syn in neurons and overexpression of iNOS promoted protein aggregation. We posit that this AAV system mimics critical protein misfolding events associated with the pathogenesis of PD.

► AAV2/1 vectors were constructed that express iNOS and α-synuclein. ► These permit DOX control of iNOS expression in a dose dependent manner. ► AAV2/1 delivered iNOS leads to robust NO production. ► iNOS overexpression induces nitration and aggregation of α-synuclein.