Identification of novel pathways that induce autophagy to enable neuroprotection

Lead Research Organisation: University of Cambridge

Abstract

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Technical Summary

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-

Publications

10 25 50
 
Description CCR5 modulation and autophagy
Amount £508,880 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2019 
End 10/2022
 
Description Development and characterisation of zebrafish models expressing a-synuclein
Amount € 478,000 (EUR)
Organisation Servier Laboratories 
Sector Private
Country France
Start 01/2019 
End 12/2020
 
Description Development and characterisation of zebrafish models expressing a-synuclein
Amount € 478,000 (EUR)
Organisation Servier Laboratories 
Sector Private
Country France
Start 01/2019 
End 12/2020
 
Description Identification of G protein-coupled receptors that modify tau clearance
Amount $200,000 (USD)
Organisation Tau Consortium 
Sector Private
Country Global
Start 10/2019 
End 11/2020
 
Description Repurposing drugs for tauopathies
Amount $200,000 (USD)
Organisation Tau Consortium 
Sector Private
Country Global
Start 10/2019 
End 11/2020
 
Description Secretion, Autophagy and their role in Neurodegeneration
Amount € 4,156,404 (EUR)
Organisation European Commission H2020 
Sector Public
Country Belgium
Start 11/2019 
End 03/2023
 
Description Small heat shock proteins and tauopathies
Amount £275,866 (GBP)
Funding ID ARUK-PG2017B-2 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2018 
End 12/2022
 
Description The Roger de Spoelberch Prize. Project component of award: Which Mendelian neurodegeration-causing genes impact autophagy?
Amount € 504,384 (EUR)
Organisation Roger de Spoelberch Foundation 
Sector Charity/Non Profit
Country Switzerland
Start 04/2018 
End 03/2021
 
Description British Council/CIC bioGUNE - public lecture in Bilbao 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact British Council/CIC bioGUNE - public lecture in Bilbao
Year(s) Of Engagement Activity 2018
 
Description Talks at international conferences 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact India-EMBO Autophagy Symposium (Bubaneswar 2017), Autophagy as a Common Pathway in Diseases (NIH, Bethesda 2018), Gordon Conference -Autophagy in Stress, Development and Disease (Il Ciocco, 2018), Interact (Munich, 2018), Autophagy and Neuroprotection (Teaching course, Venice 2018), 83rd Harden Conference Autophagy - from Molecules to Disease (Warwick 2018), Gordon conference - Neurobiology of Brain Disorders (Castelldefels, Spain, 2018), Workshop on Autophagy in model organisms (Budapest, 2018), Autophagy in the healthy and diseased brain - Lake Como School of Advanced Studies (2018), 7th International Student Symposium conducted by the International Max Planck Research School in Chemical and Molecular Biology (Dortmund) (2018)
Year(s) Of Engagement Activity 2018
 
Description Talks at international conferences 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keystone Symposium: Autophagy: From Model Systems to Therapeutic Opportunities (Santa Fe 2019), Autophagy, Inflammation & Metabolism Annual Meeting & Symposium (Albuquerque (2019), British Inflammation Research Association meeting on Autophagy (2019), FASEB - The Protein Aggregation Conference (Snowmass, 2019), Gordon Research Conference on Stress Proteins in Growth, Development and Disease (Barga, 2019), Imperial College Alzheimer's Research Network Symposium (London 2019), EMBO Autophagy Workshop 2019 (Crieff, Scotland), European Society of Neurochemistry 2019 (Milan), Basel Life - Aging and drug discovery and AI (Basel, 2019), Inaugural International Symposium of Cell Fate Determination (Shanghai 2019)
Year(s) Of Engagement Activity 2019
 
Description Talks for Medical Students societies 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact St Johns College Medical Society Cambridge (2017)
Trinity College Medical Society (2019)
Year(s) Of Engagement Activity 2017,2019
 
Description Talks for lay audiences/patients 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Addenbrooke's Hospital Huntington's disease patients (2018); Addenbrooke's Hospital Parkinson's disease patients (2018)
Year(s) Of Engagement Activity 2018