Alpha-synuclein nitration and autophagy response are induced in peripheral blood cells from patients with Parkinson disease.
Several lines of evidence implicate a central role for alpha-synuclein (aSN) in the pathogenesis of Parkinson's disease (PD). Besides rare genetic mutations, post-translational mechanisms, such as oxidative stress-related nitration, may alter the protein properties in terms of propensity to aggregate or be degraded. Our group previously described increased reactive oxygen species (ROS) production within easily accessible peripheral blood mononuclear cells (PBMCs) in PD patients compared to healthy elderly subjects. In the present work, we demonstrated a significant induction of nitrotyrosine (NT)-modifications of aSN within PBMCs derived from individuals with idiopathic PD compared to controls, while aSN protein appeared similarly expressed in the two populations. The amount of NT-modified aSN within PBMCs was positively correlated with intracellular ROS concentration and inversely related to daily dosage of levodopa, making its measurement potentially relevant for disease-intervention studies. Neither aSN expression nor its NT-modifications showed any correlation to specific REP1 genotypes, polymorphic variants within aSN gene promoter whose association to PD susceptibility may occur through the modulation of aSN protein expression. Moreover, although NT-modified aSN has been linked to enhanced propensity to aggregate, we failed to detect an increased presence of insoluble aSN aggregates in PBMCs from PD subjects relative to controls, despite a lack of changes in the ubiquitin-proteasome expression or activity. Nonetheless, a significant activation of the autophagy response was identified within PBMCs from PD individuals, which could represent a protective mechanism against abnormal protein accumulation and may explain the lack of aSN aggregation. We discuss the relevance of these findings with respect to PD pathogenesis and biomarker development. 2010 Elsevier Ireland Ltd. All rights reserved.