alpha-synuclein and 6-bromoindirubin-3--oxime

Aggrephagy is a selective autophagic degradation intracellular mechanism that clears toxic misfolded protein aggregates such as α-synuclein. Here, we identify and demonstrate that the small molecule, XCT 790 alleviates α-synuclein-mediated adverse effects in a yeast model of proteotoxicity. XCT 790 induced general autophagy and also enhanced starvation-induced autophagy. Mechanistically, we showed that XCT 790 clears toxic α-synuclein aggregates in an autophagy-dependent manner. Interestingly, XCT 790 did not demonstrate a synergistic effect on autophagy induction in the presence of another autophagy inducer such as 6-Bio.

Topics: alpha-Synuclein; Cytoprotection; Indoles; Macroautophagy; Models, Biological; Nitriles; Oximes; Protein Aggregates; Proteolysis; Saccharomyces cerevisiae; Thiazoles

Parkinson disease (PD) is a life-threatening neurodegenerative movement disorder with unmet therapeutic intervention. We have identified a small molecule autophagy modulator, 6-Bio that shows clearance of toxic SNCA/α-synuclein (a protein implicated in synucleopathies) aggregates in yeast and mammalian cell lines. 6-Bio induces autophagy and dramatically enhances autolysosome formation resulting in SNCA degradation. Importantly, neuroprotective function of 6-Bio as envisaged by immunohistology and behavior analyses in a preclinical model of PD where it induces autophagy in dopaminergic (DAergic) neurons of mice midbrain to clear toxic protein aggregates suggesting that it could be a potential therapeutic candidate for protein conformational disorders.

Topics: alpha-Synuclein; Animals; Autophagy; Brain; Cell Line; Glycogen Synthase Kinase 3 beta; HeLa Cells; Humans; Indoles; Male; Mice; Mice, Inbred C57BL; MPTP Poisoning; Neuroprotective Agents; Oximes; Protein Aggregation, Pathological; Saccharomyces cerevisiae