Lysosome-acidifying nanoparticles rescue A30P α-synuclein induced neuronal death in cellular and Drosophila models of Parkinson’s disease

Parkinson’s disease (PD) is an age-related neurodegenerative disease characterized by histopathological hallmarks of Lewy bodies formed by accumulation of α-synuclein (αSyn) and progressive loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, with clinical symptoms of motor deficits. Toxic protein accumulation of αSyn in PD is associated with autolysosomal acidification dysfunction that contributes to defective autophagy-lysosomal degradation system. While lysosome-acidifying nanoparticles have been applied as therapeutics to ameliorate dopaminergic neurodegeneration in neurotoxin mediated or αSyn aggregates induced mouse model of sporadic PD, lysosome-targeted approach has not yet been applied in synucleinopathy models of familial PD. Here, we report the first application of the new poly(ethylene tetrafluorosuccinate-co-succinate) (PEFSU)-based acidic nanoparticles (AcNPs) in A30P αSyn overexpressing SH-SY5Y cells and Drosophila models of PD. In the cellular model, we showed that AcNPs restore lysosomal acidification, promote autophagic clearance of αSyn, improve mitochondrial turnover and function, and rescue A30P αSyn induced death in SH-SY5Y cells. In the Drosophila model, we demonstrated that AcNPs enhance clearance of αSyn and rescue dopaminergic neuronal loss in fly brains and improve their locomotor activity. Our results highlight AcNPs as a new class of lysosome-acidifying therapeutic for treatment of PD and other proteinopathies in general. ### Competing Interest Statement J.Z. is a co-inventor of a patent registered with the United States Patent and Trademark Office (Patent number: US10925975B2). This patent focuses on the utilization of acidic nanoparticles as a therapeutic approach for diseases characterized by compromised lysosomal acidity. The remaining authors declare no additional competing interests.