Abstract

Intracellular protein aggregation is a feature of many late-onset neurodegenerative diseases, including Parkinson’s disease, tauopathies, and polyglutamine expansion diseases (like Huntington’s disease (HD)). Many of these mutant proteins, like that causing HD, cause disease via toxic gain-of-function mechanisms. Therefore, the factors regulating their clearance are crucial for understanding disease pathogenesis and for developing rational therapeutic strategies.

We showed that autophagy induction reduces the levels of mutant huntingtin and attenuated its toxicity in cells, and in Drosophila, zebrafish and mouse HD models. We have extended the range of intracellular proteinopathy substrates that are cleared by autophagy to other related neurodegenerative disease targets, like alpha-synuclein in Parkinson’s disease and tau in various dementias and Alzheimer’s disease. I will describe how autophagy is compromised in certain neurodegenerative diseases and focus on recent data suggesting that microglial-derived chemokines can compromise neuronal autophagy by activating CCR5 signalling. I will then consider how autophagy induction may be a powerful therapeutic approach for some of these conditions and describe different potential strategies and targets.