The selective branch of autophagy that deals with identification, capture and degradation of protein aggregates is called aggrephagy. In neurodegenration, essential protein quality control mechanisms fail as the constituent components also find themselves trapped in the aggregates. Thus, although cellular aggrephagy has the potential to be upregulated, its dysfunction further aggravates the pathogenesis.
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, the neuroprotective function of 6-Bio as envisaged by immunohistology and behavior analyses in a preclinical model of PD suggests that it could be a potential therapeutic candidate for protein conformational disorders.
Figure: Representative photomicrographs of TH+ immunostained DAergic neurons (B) in SNpc (arrow) of mouse midbrain. Placebo control cohort, MPTP-treated (23.4 mg/kg body weight), 6-Bio (5 mg/kg body weight) or both [Prophylaxis (MPTP+Pro)/Coadministration (MPTP+Co)].
