Constitutive nuclear accumulation of endogenous alpha-synuclein in mice causes motor dysfunction and cortical atrophy, independent of protein aggregation.

Abstract

BackgroundA growing body of evidence suggests that nuclear alpha-synuclein (Syn) plays a role in the pathogenesis of Parkinsons disease (PD). However, this question has been difficult to address as controlling the localization of Syn in experimental systems often requires protein overexpression, which affects its aggregation propensity. MethodsWe engineered SncaNLS mice which localize endogenous Syn to the nucleus. We characterized these mice on a behavioral, histological, and biochemical level to determine whether the increase of nuclear Syn is sufficient to elicit PD-like phenotypes. ResultsSncaNLS mice exhibit age-dependent motor deficits and altered gastrointestinal function. We found that these phenotypes were not linked to Syn aggregation or phosphorylation. Through histological analyses, we observed motor cortex atrophy in the absence of midbrain dopaminergic neurodegeneration. We sampled cortical proteomes of SncaNLS mice and controls to determine the molecular underpinnings of these pathologies. Interestingly, we found several dysregulated proteins involved in dopaminergic signaling, namely Darpp-32, which we further confirmed was decreased in cortical samples of the SncaNLS mice compared to controls via immunoblotting. ConclusionsThese results suggest that chronic endogenous nuclear Syn can elicit toxic phenotypes in mice, independent of its aggregation. This model raises key questions related to the mechanism of Syn toxicity in PD and provides a new model to study an underappreciated aspect of PD pathogenesis.