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 (alpha-syn). Moreover, nitration of alpha-syn promotes protein aggregation in disease. To model such pathological events, we constructed controllable iNOS and bicistronic alpha-syn-IRES-tTA adeno-associated virus (AAV) expression vectors. Transduction of iNOS and alpha-syn MV constructs led to nitration of alpha-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. (C) 2012 Elsevier Ireland Ltd. All rights reserved.