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

Background A growing body of evidence suggests that nuclear alpha-synuclein (αSyn) plays a role in the pathogenesis of Parkinson’s disease (PD). However, this question has been difficult to address as controlling the localization of αSyn in experimental systems often requires protein overexpression, which affects its aggregation propensity. Methods We engineered Snca NLS mice which localize endogenous αSyn to the nucleus. We characterized these mice on a behavioral, histological, and biochemical level to determine whether the increase of nuclear αSyn is sufficient to elicit PD-like phenotypes. Results Snca NLS mice exhibit age-dependent motor deficits and altered gastrointestinal function. We found that these phenotypes were not linked to αSyn aggregation or phosphorylation. Through histological analyses, we observed motor cortex atrophy in the absence of midbrain dopaminergic neurodegeneration. We sampled cortical proteomes of Snca NLS 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 Snca NLS mice compared to controls via immunoblotting. Conclusions These results suggest that chronic endogenous nuclear αSyn can elicit toxic phenotypes in mice, independent of its aggregation. This model raises key questions related to the mechanism of αSyn toxicity in PD and provides a new model to study an underappreciated aspect of PD pathogenesis. ### Competing Interest Statement The authors have declared no competing interest. * ### List of Abbreviations 5-HIAA : 5-hydroxyindoleacetic acid αSyn : alpha-synuclein DA : dopamine Darpp-32 : dopamine- and cAMP-regulated neuronal phosphoprotein DOPAC : 3,4-dihydroxyphenylacetic acid GO : Gene ontology HPLC : high-performance liquid chromatography HVA : homovanillic acid NLS : nuclear localization signal PD : Parkinson’s disease PV : parvalbumin SNc : Substantia Nigra pars compacta TH : tyrosine hydroxylase