Autophagy and Neurodegeneration
University of Cambridge (UK)
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.
The two major intracellular protein degradation pathways are the ubiquitin-proteasome system and (macro)autophagy. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded.
I will briefly describe the basic biology of autophagy before outlining its roles in neuro-degeneration. We showed that the autophagy inducer, rapamycin, reduced the levels of mutant huntingtin and attenuated its toxicity in cells, and in Drosophila 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 Parkinson's disease. While autophagy induction is protective in models of various neurodegenerative diseases, certain other conditions are associated with compromised autophagy. I will discuss how genetic variants in Parkinson's disease, Alzheimer's disease and polyglutamine diseases impact on autophagosome biogenesis.