Disrupting the interaction between AMBRA1 and DLC1 is a promising therapeutic strategy for neurodegeneration that prevents apoptosis while enhancing autophagy and mitophagy

Abstract

Activating molecule in Beclin1-regulated autophagy (AMBRA1) has critical roles in autophagy, mitophagy, cell cycle regulation, neurogenesis and apoptosis. Dysregulation of these processes are hallmarks of various neurodegenerative diseases and therefore AMBRA1 represents a potential therapeutic target. The flexibility of its intrinsically disordered regions allows AMBRA1 to undergo conformational changes and thus perform its function as an adaptor protein for various different complexes. Understanding the relevance of these multiple protein-protein interactions will allow us to gain information about which to target pharmacologically. To compare potential AMBRA1 activation strategies we have designed and validated several mutant constructs (ACTA, TAT, WD40 and S1014) in addition to characterising their effects on proliferation, apoptosis, autophagy and mitophagy in SHSY5Y cells. AMBRA1TAT, which is a mutant form of AMBRA1 that cant interact with dynein light chain (DLC)1 at the microtubules, produced the most promising results. Indeed, overexpression of this mutant protected cells against apoptosis and induced autophagy and mitophagy in SHSY5Y cells in addition to enhancing the switch from quiescence to proliferation in mouse neural stem cells. Future studies should focus on designing compounds that inhibit the protein-protein interaction between AMBRA1 and DLC1 and thus have potential to be used as a drug strategy to treat neurodegeneration.