Prof David Rubinsztein
Wellcome Trust
United Kingdom
Autophagy in health and disease.
Wellcome Trust
4,542,895
01/01/12
6.0
Neurodegenerative disease in general
Alzheimer | Cognitive impairment | Dementia | Huntington | Neurodegen | Parkinson
Intracellular protein misfolding/aggregation characterises many late-onset neurodegenerative diseases, including Alzheimer s disease, Parkinson s disease, tauopathies, and Huntington s disease (HD)). The mutations causing HD and many related diseases confer novel toxic functions on the specific protein. Thus, it is important to understand the factors regulating the levels of these proteins. (Macro) autophagy clears long-lived proteins and organelles by forming autophagosomes that engulf p ortions of cytoplasm. Autophagosomes ultimately fuse with lysosomes, where their contents are degraded. Autophagy regulates the levels of intracytoplasmic aggregate-prone proteins that cause neurodegenerative diseases, including HD. Autophagy upregulation may attenuate diseases like HD, and possibly tuberculosis. Autophagy inhibition slows growth of existing tumors, and may also contribute to pathology in various neurodegenerative diseases. I aim to: Discover novel autophagy-modulating dr ugs/pathways and test their clinical relevance in models of neurodegenerative diseases, tuberculosis and cancer. Test if there are beneficial/deleterious effects of constitutive autophagy upregulation in vertebrates. Develop methods to infer autophagic flux in vivo. Understand how autophagy compromise causes pathology. Identify novel autophagy-regulating mechanisms and investigate possible disease relevance. These studies will help the understanding of the relationship betwee n autophagy, normal physiology and disease, and will provide proof-of-principle for autophagy-modulating strategies as therapies for a range of conditions.