(Macro) autophagy is a bulk degradation process that mediates the clearance of long-lived proteins and organelles. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded. Initially, we discovered that autophagy is a key regulator of the levels of intracytoplasmic aggregate-prone proteins that cause neurodegenerative diseases. We have shown that autophagy-upregulating drugs enhance the clearance of mutant huntingtin, mutant ataxin 3 (that causes spinocerebellar ataxia), and mutant and wild-type forms of tau in a range of in vivo models (flies, zebrafish and mice) and attenuate the toxicities of these proteins in these in vivo models.
When we initiated our studies, the only known pharmacological way of inducing autophagy chronically was with rapamycin. Although rapamycin is designed for long-term use, it has side effects which may make it unattractive to patients who may need to take the drug for decades. Thus, we have embarked on a series of studies to identify novel autophagy-upregulating compounds and have discovered pathways that are independent of the target of rapamycin. We have shown that drugs acting on such pathways are protective in fly, zebrafish and mouse models of Huntington's disease. We are about to embark on a safety trial with one of these drugs, rilmenidine, in Huntington's disease patients, in collaboration with Dr Roger Barker (Clinical Neurosciences).
Importantly, our studies have also revealed that antioxidants, which are widely believed to be protective in neurodegenerative disease, impair autophagy and worsen the phenotype in various Huntington's disease models. This provides a new insight into possible side effects of such drugs and may explain their lack of efficacy in trials in Huntington's disease patients, to date.