LETC Inhibits Α-Syn Aggregation and Ameliorates Motor Deficiencies in the L62 Mouse Model of Synucleinopathy

Alpha-Synuclein (alpha-Syn) aggregation is a pathological feature of synucleinopathies, neurodegenerative disorders that include Parkinson's disease (PD). Here, we explored the efficacy of N,N,N ' ,N ' -tetraethyl-10 H -phenothiazine- 3,7-diamine dihydrochloride (LETC), a protein aggregation inhibitor, on alpha-Syn aggregation. In both cellular models and transgenic mice, alpha-Syn aggregation was achieved by the overexpression of full-length human alpha-Syn fused with a signal sequence peptide. alpha-Syn accumulated in transfected DH60.21 neuroblastoma cells and alpha-Syn aggregation was inhibited by LETC with an EC 50 of 0.066 +/- 0.047 mu M. Full-length human alpha-Syn overexpressing Line 62 (L62) mice accumulated neuronal alpha-Syn that was associated with a decreased motor performance in the open field and automated home cage. LETC, administered orally for 6 weeks at 10 mg/kg significantly decreased alpha-Syn-positive neurons in multiple brain regions and this resulted in a rescue of movement deficits in the open field in these mice. LETC however, did not improve activity deficits of L62 mice in the home cage environment. The results suggest that LETC may provide a potential disease modification therapy in synucleinopathies through the inhibition of alpha-Syn aggregation.