Expression of transduced Nucleolin promotes the clearance of accumulated alpha-synuclein

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Abstract Background Alpha-synuclein (αSyn) is a major component of Lewy bodies, which are known to be a pathogenic marker of Parkinson’s disease (PD). The accumulation of αSyn is caused by dysfunctions in protein degradation machinery. The reinforcement of αSyn degradation is a potential therapeutic target of PD since accumulated αSyn is responsible for the pathogenesis of PD. Nucleolin (NCL) is essential for forming nucleolar structure. The function of NCL is correlated with oxidative stress-mediated cell death. A previous study demonstrated that NCL was reduced in PD brains, and overexpression of NCL alleviated rotenone-induced neural toxic effects. Knockdown of NCL had the opposite effect. These results suggest that the malfunctioning of NCL would exacerbate PD pathology. Thus, we hypothesized that the introduction of ectopic NCL could rescue the α-synucleinopathy in PD. Methods We tested whether ectopic expression of NCL facilitates the clearance of αSyn. The Ectopic expression of NCL was accomplished by the transfection of GFP or GFP-NCL in mouse embryonic fibroblasts (MEF) or transduction of green fluorescent protein (GFP) or GFP-NCL using lentivirus in rat primary cortical neuron. We also investigated whether the expression of GFP or GFP-NCL in mouse substantia nigra alleviates the PD pathology derived by αSyn aggregates. Results The expression of NCL enhanced the clearance of αSyn accumulation or aggregates in MEF and rat primary cortical neurons. The activity of autophagy-lysosome pathway was enhanced by NCL expression. The transduction of NCL in the substantia nigra, which was co-injected with αSyn fibrils, rescued PD manifestations. Conclusions The elevation of NCL levels may reflect a therapeutic strategy for α-synucleinopathy in PD.

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