Identification of novel pathways that induce autophagy to enable neuroprotection

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The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019.

(Macro)autophagy is a major route for the degradation of intracytoplasmic contents, including proteins and organelles, like mitochondria. The earliest morphologically recognisable autophagic intermediates are phagophores, which evolve into double-membraned, sac-shaped structures. After phagophore edges extend and fuse, engulfing a portion of cytoplasm, they become autophagosomes, which deliver their contents to lysosomes for degradation.
My laboratory discovered that autophagy is critical for the degradation of diverse toxic intracytoplasmic aggregate-prone proteins that cause neurodegenerative diseases, including Huntington’s disease (HD), mutant alpha-synuclein (forms of Parkinson’s disease (PD)), and tau. We discovered that autophagy-upregulating drugs enhance the clearance of such proteins and thereby attenuate their toxicities in Drosophila, zebrafish and mice (Hum Mol Genet 2002; 11, 1107-1117; J Biol Chem 2003; 278, 25009-25013; Nature Genet 2004; 36, 585-595; Hum Mol Genet 2006; 15, 433-442), a strategy subsequently validated by many groups. Now autophagy is considered an important neurodegeneration target by leading pharma companies. A major thrust of my laboratory has been to identify novel pathways regulating autophagy, as some of these may be druggable or may provide important insights into disease processes (e.g. Nat Chem Biol 2007; 3, 331-338; Nat Chem Biol 2008; 4, 295-305; Mol Cell 2015; 57, 219-234; Nature Commun 2015; 6, 8045). This programme, which is distinct from my funded/pending grants, will use cutting-edge strategies and collaborations (Emmanouil Metzakopian (Sanger Institute), Madan Babu (MRC-LMB) and Jonathan Clarke (ARUK Cambridge DDI) to identify novel autophagy-