IDENTIFICATION OF GENERIC SUPRESSORS OF PROTEINOPATHIES

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.

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.

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.