Professor David Rubinsztein
Autophagy and neurodegeneration
To understand the biology of diseases associated with protein misfolding and intracellular aggregation, using Huntington’s disease (HD) as a paradigm.
Intracellular protein misfolding/aggregation are features of many late-onset neurodegenerative diseases, called proteinopathies. These include Alzheimer’s disease, Parkinson’s disease, tauopathies, and polyglutamine expansion diseases (like Huntington’s disease (HD) and various spinocerebellar ataxias (SCAs)). Currently, there are no effective strategies that slow/ prevent the neurodegeneration resulting from these diseases in humans.
We are currently employing a range of approaches to address this issue, including conventional biochemistry and cell biology, zebrafish genetic knockdowns and genome-wide Drosophila modifier screens. We are trying to identify pathways that may be have broad relevance to a range of neurodegenerative diseases (e.g. Sarkar et al (2011) Mol Cell 43:19-32).
To develop therapeutic strategies for these diseases.
The mutations causing HD and many proteinopathies confer novel toxic functions on the specific protein, and disease severity frequently correlates with expression levels. Thus, it is important to understand the factors regulating the levels of these aggregate-prone proteins.
(Macro) autophagy is a bulk degradation process that mediates the clearance of long-lived proteins and organelles (reviewed in Rubinsztein et al (2011) Cell 146:682-695). Autophagosomes are formed by double-membraned structures, which engulf portions of cytoplasm. Autophagosomes ultimately fuse with lysosomes, where their contents are degraded (see schematic below).
We have become increasingly involved in studying autophagy, since the time of our discovery that it regulates of the levels of intracytoplasmic aggregate-prone proteins that cause many neurodegenerative diseases, including Huntington’s disease, point mutations in alpha-synuclein (causing forms of Parkinson’s disease), and wild-type and mutant forms of tau (causing various dementias) (reviewed in Fleming et al. (2011) Nature Chemical Biology 7:9-17). The clearance of such substrates is retarded in cell models when autophagy is compromised. For Huntington’s disease and a range of related neurodegenerative diseases, we are pursuing our findings that the toxicity of these proteins in cells, Drosophila, zebrafish and mice can be alleviated by enhancing their removal by autophagy (Ravikumar et al, (2004) Nature Genetics 36: 585-595). We are trying to identify safe and effective strategies for exploiting autophagy upregulation in order to enhance the removal of the toxic intracytoplasmic proteins that cause many of these diseases ( e.g. Sarkar et al (2007) Nature Chemical Biology 3: 331-338; Williams et al (2008) Nature Chemical Biology 4: 295-305).
To contribute to the understanding of the cell biology of autophagy and its relevance to human physiology and disease, with a focus on the nervous system.
We have identified the plasma membrane as a source of autophagosome membrane (Ravikumar et al (2010) Nature Cell Biology 12:747-757) and have characterised early events in autophagosome biogenesis (e.g. Moreau et al (2011) Cell 146:303-317). We have studied how lysosomal positioning regulates autophagy (Korolchuk et al (2011) Nature Cell Biology 13:453-460).
We have found that autophagy may be inhibited in various neurodegenerative diseases (e.g. Winslow et al (2010) J Cell Biol 190:1023-1037) and have been trying to elucidate the pathological consequences of autophagy compromise - our data suggest that autophagy inhibition impairs flux through the ubiquitin-proteasome degradation pathway (Korolchuk et al (2009) Molecular Cell 33:517-527).
- Wellcome Trust Principal Fellowship
- National Institute for Health Research - Biomedical Research Unit
- Wellcome Trust/MRC Neurodegenerative Diseases Strategic Award (co-applicant)
- EU Framework VII – MEFOPA, TreatPolyQ
- BBSRC/Lilly CASE Studentship
- MRC Centres of Excellence in Neurodegeneration.
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