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.
In this talk, I will discuss how genetic lesions causing neurodegeneration impact autophagy at different stages of the pathway and will describe some of our attempts to identify therapeutic targets. I will focus on describing how the Huntington’s disease mutation and mutations causing Parkinson’s disease and tauopathy impact autophagy. I will describe how these may act via either cell-autonomous and non-cell-autonomous mechanisms. Then I will describe how autophagy is synthetic lethal with defective proteasome and nuclear pore function - phenomena that can be explained by our observation that autophagy-deficient cells shuttle cytoplasmic autophagic substrates to the nucleus for proteasomal degradation. This proteostatic control mechanism appears to be compromised in Huntington’s disease, where there is both defective autophagy and altered nuclear pore function, suggesting that some of the pathology in this disease may be due to combined defects in apparently distinct pathways.