Aminochrome-Induced Disruption of Autophagosome-Lysosome Fusion: Implications for Protein Aggregation in Parkinson's Disease

Aminochrome, an endogenous neurotoxin, has been suggested that it is implicated in the loss of dopaminergic neurons that contain neuromelanin in the nigrostriatal system in Parkinson's disease. While aminochrome-induced oxidative stress, as well as its inhibitory effects on microtubule polymerization in neuronal models, are well documented, its impact on autophagosome–lysosome fusion and protein aggregation remains unexplored. The aim of this research was to evaluate the effects of aminochrome on the fusion between autophagosomes and lysosomes, and the accumulation of protein aggregated using SH-SY5Y cells differentiated into dopaminergic neurons. Our findings reveal that aminochrome like vinblastine, delays the fusion of autophagosomes with lysosomes, as evidenced by decreased colocalization of LC3β-LAMP1. This effect was also observed after the addition of autophagy inductors such as rapamycin and trehalose. Moreover, rapamycin and trehalose mitigate aminochrome-induced cell death, whereas vinblastine exacerbates it. Bafilomycin A1, despite reducing LC3β-LAMP1 colocalization, offers protection against aminochrome-induced cytotoxicity. These disruptions in autophagosome-lysosome fusion are associated with accumulation of perinuclear vimentin and ubiquitin aggregates together with increased colocalization between vimentin and ubiquitin. Interestingly, the presence of ubiquitin aggregates at the nuclear level were also observed. It is postulated that the effect of aminochrome on the microtubule network, particularly inhibition of the autophagosome-lysosome fusion and the accumulation of protein aggregates, could be one of the critical events that lead to cell death. Our findings underscore the therapeutic potential of targeting microtubule stabilization and autophagy/UPS induction in Parkinson's disease, an energy-dependent process, highlighting the need for further research into nuclear proteotoxicity mechanisms.