Understanding the role of RNA in the molecular mechanisms of FTD/ALS

Lead Research Organisation: King's College London

Abstract

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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.

Increasing evidence suggests that RNA plays an active role in a number of neurodegenerative diseases, either directly through the sequestration of RNA binding proteins bound to RNA foci or indirectly through aberrant RNA processing caused by the aggregation of RNA binding proteins1. It has been shown for instance that in
myotonic dystrophy, multiple ataxias and Huntington’s disease, primary transcripts containing expanded trinucleotide regions form intranuclear foci that sequester and inactivate key RNA processing proteins. RNA/protein interactions facilitate the conversion of the a-rich prion protein (PrPC) into its infectious ß-rich insoluble form (PrPSc) in Creutzfeldt-Jakob disease. In Alzheimer’s disease, translation of aggregation-prone proteins is regulated by iron-dependent ribonucleo-protein interactions. The most striking examples are
frontotemporal dementia (FTD) and of amyotrophic lateral sclerosis (ALS) where TDP-43 and FUS mislocalize and aggregate. Both are RNA binding proteins involved in regulating RNA transcription, splicing, stabilization, transport and translation2. RNA-binding protein sequestration (bound to RNA foci or into oligomers) potentially affects the processing of a large number of different RNA molecules leading to the dysfunction of multiple cellular processes, which leads to neuronal cell death. Several proteins involved in neurodegenerative diseases have also been shown to interact with their own cognate mRNAs in an important self-regulatory mechanism that controls translation through a negative feedback loop: when protein concentration is high, binding to the transcript inhibits translation through an editing event that initiates nonsense mediated decay, thus reducing protein levels. A dual role of RNA in function and disease well agrees with the concept that
aggregation is a competing pathway to normal function, as we observed for members of the family of polyglutamine proteins associated with spinocerebellar ataxias3. These observations directly suggest that the natural partners of a protein are the best candidates to compete out pathological aggregation and may represent a powerful strategy to design disease-specific molecules which may emulate the natural partners and that could be used as therapeutic lead compounds.

Publications

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Title nanoFTIR 
Description We have used in cell nanoFTIR to study the metabolic landscape of disease 
Type Of Material Technology assay or reagent 
Year Produced 2020 
Provided To Others? Yes  
Impact It allows to follow the metabolic status of cells from patients 
 
Title nanosensors for the study of cell metabolism 
Description We coupled Atomic force microscopy with nanosensors to study the metabolism of cells 
Type Of Material Technology assay or reagent 
Year Produced 2019 
Provided To Others? Yes  
Impact We have used this non invasive technique to study the effect of frataxin overexpression on the cell metabolism 
 
Description AD-PAINTS 
Organisation University of Edinburgh
Department Edinburgh Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution We are designing RNA aptamers for the study of TDP-43 aggregates in vivo
Collaborator Contribution The partner Matthew Horrocks has experience in super-resolution microscopy.
Impact We are currently writing a manuscript meant for Nature Methods. We are also submitting an application for ADDF.
Start Year 2017
 
Description Rational design of RNA aptamers 
Organisation Italian Institute of Technology (Istituto Italiano di Tecnologia IIT)
Department Neuroscience and Brain Technologies IIT
Country Italy 
Sector Academic/University 
PI Contribution We are developing RNA aptamers against TDP-43
Collaborator Contribution The partner Gian Gaetnao Tartaglia is the author of the software used for the prediction.
Impact We have held together a grant from MNDA and published four papers together. We are now in the process of sending off a manuscript and a grant application to ADDF.
Start Year 2016
 
Description The mechanism of protein aggregation 
Organisation Moscow State University
Department Biochemistry Department
Country Russian Federation 
Sector Academic/University 
PI Contribution We have been collaborating on the effects of metals on the aggregation of the Abeta peptides.
Collaborator Contribution They produced the peptide and analysed the data collected in London
Impact We have been accepted a paper in Scientific reports.
 
Description rational Design of antibodies against TDP-43 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Design new antibodies against post-translationally modified TDP-43
Collaborator Contribution Dr Aprile from Imperial College has a long experience in antibody design.
Impact Biophysics, structural biology, bioinformatics
Start Year 2019
 
Description Seminar to International Rotary Club 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The meeting was to sensibilise general audience about dementia.
Year(s) Of Engagement Activity 2020