Frontotemporal dementia disease mechanisms
Award Number
UKDRI-1006Programme
IntramuralStatus / Stage
ActiveDates
1 September 2017 -31 December 2021
Duration (calculated)
04 years 03 monthsFunder(s)
MRC (UKRI)Funding Amount
£722,236.00Funder/Grant study page
MRC UKRIContracted Centre
UK Dementia Research Institute at University College LondonContracted Centre Webpage
Principal Investigator
Dr Adrian IsaacsPI Contact
a.isaacs@ucl.ac.ukWHO Catergories
Tools and methodologies for interventionsUnderstanding risk factors
Disease Type
Frontotemporal Dementia (FTD)CPEC Review Info
| Reference ID | 245 |
|---|---|
| Researcher | Reside Team |
| Published | 12/06/2023 |
Data
| Award Number | UKDRI-1006 |
|---|---|
| Status / Stage | Active |
| Start Date | 20170901 |
| End Date | 20211231 |
| Duration (calculated) | 04 years 03 months |
| Funder/Grant study page | MRC UKRI |
| Contracted Centre | UK Dementia Research Institute at University College London |
| Contracted Centre Webpage | |
| Funding Amount | £722,236.00 |
Abstract
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. C9orf72 repeat expansions are a common cause of neurodegenerative disease Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders for which no effective therapies exist. Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of both FTD and ALS, making them one of the most frequent single gene causes of neurodegeneration identified to date. Whilst < 33 GGGGCC repeats occur in the healthy general population, with just 2 repeats being the most common, C9orf72 FTD/ALS (C9FTD/ALS) cases carry 500- 4400 repeats. C9orf72 repeat expansions can cause neurodegeneration through arginine-rich proteins The expanded repeats have been hypothesised to cause disease by three non-mutually exclusive mechanisms: i) reduced expression of C9orf72, ii) toxic sense and antisense repeat RNA species that sequester key RNA binding proteins or iii) toxic dipeptide repeat (DPR) proteins, generated by repeat associated non-ATG translation. The GGGGCC repeat can be translated in all sense and antisense frames, two of which code for the same DPR, resulting in five DPR proteins: poly-glycine-arginine (GR), polyproline- arginine (PR), poly-glycine-alanine (GA), poly-glycine-proline (GP), and poly-proline-alanine (PA). We have made several key contributions to understanding C9FTD/ALS 1-4 and have provided evidence that loss of function is not the primary cause of disease 3. In addition, complete knockout of C9orf72 in mice does not lead to neurodegeneration, but rather to immune defects 5, indicating that loss of function may modulate the disease process, but is not the key driver of disease. We have therefore focussed on gain of function mechanisms.
Aims
The study aims to develop markers that will help with early diagnosis of FTD and understand the progression of disease. It also aims to understand the complex symptoms of FTD and how these relate to changes in brain function and structure. The study is recruiting people with behavioural frontotemporal dementia and primary progressive aphasia (the language form of FTD) as well as people who have motor symptoms such as parkinsonism or motor neurone disease.