Proteostatic mechanisms in FTD and ALS

Lead Research Organisation: King's College London

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

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.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are
neurodegenerative disorders that appear as distinct clinical phenotypes but can share a common genetic aetiology and molecular pathology. TDP-43 aggregates are the hallmark pathology in 95% of all ALS and tau-negative FTD cases, affecting predominantly motor neurons in the spinal cord, brainstem, and motor cortex in ALS and neurons in the frontal and temporal lobes in FTD. TDP-43 is a DNA and RNA binding protein that regulates RNA transcription, splicing, trafficking and translation. Knock-down and overexpression
of TDP-43 are both neurotoxic. Mutations in >14 genes account for ~40-60% of familial and ~10% of sporadic ALS and FTD cases. Most gene mutations contribute to the aggregation of TDP-43 in the cytoplasm and/or depletion of TDP-43 in the nucleus. Our discovery that mutations in the gene encoding TDP-43 are neurotoxic confirmed that TDP-43 aggregation/depletion is the primary disease mechanism and that prevention of aggregation and the clearance of aggregates is a major therapeutic target1.

Publications

10 25 50
 
Description Exome sequencing in motor neuron disease: bioinformatic analyses and biological validation of novel variants 
Organisation Motor Neurone Disease Association (MND)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution ALS research excellence
Collaborator Contribution financial
Impact Publication of new ALS genes
Start Year 2015
 
Description Generation and characterisation of induced pluripotent stem cells from ALS lymphoblasts to model disease pathogenesis and advance drug discovery 
Organisation Motor Neurone Disease Association (MND)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Research excellence
Collaborator Contribution Financial and access to lymphoblast cell lines
Impact Nil yet as just started
Start Year 2015
 
Description Investigating the role of autophagy and the UPS in TDP-ALS 
Organisation Motor Neurone Disease Association (MND)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution ALS pathobiology
Collaborator Contribution Financial Support
Impact None
Start Year 2015
 
Description Alinda Fernandes gave Lewisham Health Lectures at Lewisham Library - Talk Title: Alzheimer's Disease and Dementia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The talk was received very good feedback and triggered a series of stimulating conversations
Year(s) Of Engagement Activity 2017
 
Description Alinda Fernandes poster presentation at MNDA Symposium Boston (2017) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The poster was presented to mainly scientists during the poster session which enabled new collaborations.
Year(s) Of Engagement Activity 2017
 
Description Eva So Poster presentation at the Edmond J. Safra Memorial Lecture and Reception 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Poster presentation to the audience and interactive communication and discussion about research work. Event included presentation and talks highlighting the modern day approach to research in Parkinson's and other neurodegenerative diseases and the frontline advances being made by different researchers, followed by question and answer session with the audience and direct communication at the poster reception.
Year(s) Of Engagement Activity 2017
 
Description Graham Cocks Poster submission - Poster presentation on CRISPR work for the 4th Genome editing conference, Oxford (GEOX 2018) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation of a poster to international scientists.
Year(s) Of Engagement Activity 2018
 
Description Jenny Greig Legacy fundraising event 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact People interested in supporting the MNDA came for a day of presentations to see the facility and the work that takes place here.
Year(s) Of Engagement Activity 2018
 
Description Jenny Greig poster presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Poster presentation at Stem Cell conference at Edinburgh University
Year(s) Of Engagement Activity 2017
 
Description Jenny Greig poster presentation at MNDA conference in Boston 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation at MNDA conference in Boston
Year(s) Of Engagement Activity 2017
 
Description MND Genetics and Therapies 
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 Presentation on MND genetics and therapies to Palliative Health Care Professionals and members iof the public at a public centre
Year(s) Of Engagement Activity 2018
 
Description Public Lecture to Aotea Centre, Auckland New Zealand 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Lecture on motor neuron disease therapies to lay audience
Year(s) Of Engagement Activity 2018
 
Description Review of Dementia Research Institute at King's 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk on the Dementia Research activity at Kings
Year(s) Of Engagement Activity 2018