IDENTIFICATION OF GENERIC SUPRESSORS OF PROTEINOPATHIES

Lead Research Organisation: University of Cambridge
Department Name: Cambridge Institute for Medical Research

Abstract

We aim to identify genes that reduce the toxicity of a wide range of different mutant proteins that cause neurodegeneration. We will identify such genes and pathways by performing a bioinformatics analysis of existing genetic screens for modifiers in lower organisms (from yeast to Drosophila), as well as targeted studies in all systems, including high confidence genome wide association study hits for Alzheimer's and Parkinson's disease and ALS. Using multiple data sources, we will identify
hallmark features of "generic modifiers" and use computational methods to identify
new modifiers, which will then be tested for efficacy in fruit fly models of different diseases, like Huntington's disease and forms of dementia. Novel modifiers showing efficacy in more
than one disease will be studied in cell models and fruit flies to identify mechanisms of
action. The identification of such "generic" supressors and their mechanisms would
create a list of high priority targets for consideration for therapeutic development and/or
detailed mechanistic analyses, as these would be acting on a range of diseases and are
expected to affect core processes.

Technical Summary

We aim to identify "generic" suppressors of neurodegeneration caused by different
intracellular proteinopathies by performing a bioinformatics meta-analysis of existing
genetic screens for modifiers in lower organisms (from yeast to Drosophila), as well as
targeted studies in all systems, including high confidence GWAS hits for Alzheimer's and
Parkinson's disease and ALS. Using multiple data sources, including functional genomics
data, such as protein interaction or mRNA expression profiling data, we will identify
hallmark features of generic modifiers and train machine learning classifiers to identify
new modifiers, which will then be tested for efficacy in Drosophila models of different
proteinopathies (HD, TDP-43, tauopathies). Novel modifiers showing efficacy in more
than one disease will be studied in cell models and Drosophila to identify mechanisms of
action. The identification of such "generic" supressors and their mechanisms would
create a list of high priority targets for consideration for therapeutic development and/or
detailed mechanistic analyses, as these would be acting on a range of diseases and are
expected to affect core processes.

Planned Impact

The potential beneficiaries of our research include patients with neurodegenerative diseases and their families, clinicians treating these families, other scientists working on neurodegenerative disease, and biotech and pharma companies with interests in these fields. They will benefit if we identify novel pathways regulating neurodegenerative disease, especially if these are druggable.

This will be of benefit to the pharma/biotech sector, as the identification of novel targets and pathways is a critical first step towards rational therapeutic strategies. This is particularly relevant to neurodegenerative diseases, which are becoming an increasing economic, healthcare, social care, and social burden on societies which are living longer. If we have success with our studies, and if we identify pathways that are relevant to treatment/disease progression, the such programmes would ultimately benefit society at large, and not only the specific patients and their families

The identification of such pathways may also have relevance to the development of more powerful biomarkers for some of these diseases. This is an area of need, since current clinical trial strategies are handicapped by the need for large patient cohorts, and experimental medicine-type studies using biomarkers may assist in prioritising the potential interventions that should be tested in such large cohorts. The beneficiaries in this context would be clinician-scientists and ultimately patients.
The staff employed on this project will hopefully acquire a range of relevant scientific and transferable skills (like their predecessors) and be highly employable in various sectors. Staff working in our labs have moved on to good positions in academia (lectureships, senior and intermediate fellowships, postdoc positions at prestigious institutions like Harvard and MIT), as well as good positions in pharma.

Publications

10 25 50
 
Description 15 international conferences in 2016 - speaker 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact conference presentations at internationa; meetings: Black Forest Winter Conference: "Autophagic Membrane Trafficking & Dynamics in Ageing and Disease" (Freiburg 2016), CHDI's 11th Annual Therapeutics Conference (Palm Springs 2016), International Congress of Human Genetics (Kyoto, 2016), Neuroscience School of Advanced Studies - Autophagy and neuroprotection (Cortona - lecture course 2016), International Society for Developmental Neuroscience (2016, Juan les Pins), European Neuroscience Institute 15th Anniversary Symposium (Gottingen 2016), Keystone Autophagy symposium (Whistler, 2016), Mitochondria: balancing health and disease (London 2016), Nobel conference - The Cell Cycle and Cell Death in Disease (Stockholm, 2016), Centre for Translational Cell Research opening sympiosium (Freiburg 2016), PhD graduate Symposium Cologne Graduate School of Aging Research (2016), Cold Spring Harbor meeting: Neurodegenerative Diseases: Biology & Therapeutics (Cold Spring Harbor 2016), Milner Therapeutics Institute Symposium (Cambridge 2016), 26th Annual Meeting of the Network for European CNS Transplantation & Restoration (NECTAR), Cambridge 2016)
Year(s) Of Engagement Activity 2016
 
Description Public talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact More than 200 people at talk, youtube film

interest in field
Year(s) Of Engagement Activity 2013
 
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 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 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