An interdisciplinary approach to unravel mechanistic understanding of Frontotemporal lobar degeneration

Lead Research Organisation: University of Manchester
Department Name: School of Biological Sciences

Abstract

Dementia causes enormous personal hardship and costs the UK ~£23 billion every year. The second most common form is Frontotemporal lobar degeneration (FTLD). About 40% of FTLD cases have genetic causes, with >8% involving abnormal intronic GGGGCC hexanucleotide repeat expansions in the C9orf72 gene which can additionally cause motor neuron disease (OMIM #105550). These pathological expansions are actively transcribed and, via bidirectional repeat-associated non-ATG (RAN) translation, generate 5 different aggregate-forming GA, GR, PR, GP and AP dipeptide repeat proteins (DPRs).This project will gain new understanding of this type of FTLD by unravelling neurodegenerative pathomechanisms of DRPs through using interdisciplinary approaches. We will focus on the hypothesis that toxicity is caused by DRP structure, comparable to amyloid plaques in Alzheimer's disease. The project will capitalise on the complementary expertises of the three supervisors, and a readily available, unique set of 4 GFP-tagged constructs with high, pathologically relevant repeat numbers. The detailed aims and outcomes are:

To generate purified DRPs and perform biochemical and biophysical analyses, in order to understand the reasons for their toxicity and identify useful therapeutic strategies which will benefit patients and their families.
To generate transgenic Drosophila fly stocks to obtain primary neurons expressing the four DRPs. We will use powerful fly genetics and well established cell biological approaches to identify the neuronal death pathway and of the DRP-induced pathomechanisms upstream.
There is substantial proof-of-principle for the use and translational potential of Drosophila To validate identified DRP pathomechanisms in mammalian contexts, we will carry out complementary experiments using well established DRP models in SH-SY5Y cells and inducible neuronal cell lines.
This project is highly interdisciplinary, with the analysis of the dipeptide repeat proteins spanning systems from in vitro solvents to human and fly cell lines. The student will receive a broad training in characterisation of polypeptide structure and aggregation, cell culture, fly and human genetics, and cell biology, all in the context of genetic disease and neurodegeneration.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
MR/N013751/1 30/09/2016 29/09/2025
1916530 Studentship MR/N013751/1 30/09/2017 29/09/2021 Joanne Sharpe
 
Title Novel Drosophila model of C9orf72 dipeptide repeat proteins 
Description Flies expressing 1000 repeat DPRs in the nervous system. A more pathologically relevant model for studying mechanisms of frontotemporal dementia / motor neurone disease caused by the C9orf72 mutation. 
Type Of Material Model of mechanisms or symptoms - non-mammalian in vivo 
Year Produced 2019 
Provided To Others? No  
Impact N/A.. paper pending submission 
 
Description Alzheimer's Research UK Fundraising Group Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 50 members of a fundraising group attended an information and fundraising event. 30 minute talk about my research with questions and discussion afterwards. Feedback very positive and the attendees felt reassured and positive.
Year(s) Of Engagement Activity 2019