University of Dundee

“Perturbed TDP-43 auto regulation in novel mouse and human knock-in models of ALS-FTD”

Event Date: 
Wednesday, September 12, 2018 - 13:00 to 14:00
Event Location: 
CTIR Sir Kenneth and Lady Noreen Murray Seminar Room
Host: 
Professor Miratul Muqit
Event Speaker: 
Dr Jemeen Sreedharan
Institution: 
King's College London
Event Type: 
Seminar
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MRC Protein Phosphorylation and Ubiquitylation Informal Seminar

 

Biography

Dr Sreedharan developed an early interest in neurodegeneration during his time as a medical student at King’s College London. Following medical training he conducted doctoral studies in the lab of Prof Christopher Shaw at the IoPPN, identifying TDP-43 mutations in patients with ALS. He then completed neurology training before obtaining an MRC Intermediate Clinical Fellowship to model TDP-43 mutations in vivo. The first two years of this Fellowship were spent at the University of Massachusetts Medical School, Worcester, USA. Here, he worked in the lab of Prof Marc Freeman to develop a novel method of screening for modifiers of TDP-43 toxicity using Drosophila melanogaster (the fruitfly). He also worked in the lab of Prof Robert H. Brown Jr to develop a novel TDP-43 knock-in mouse model of disease. In 2014 Dr Sreedharan returned to the UK to work with Prof Michael Coleman at the Babraham Institute in Cambridge to continue his studies into TDP-43-mediated neurodegeneration. In June 2017 Dr Sreedharan started his independent group at the Maurice Wohl Clinical Neuroscience Institute thanks to a generous van Geest Post Doctoral Fellowship in Neurodegeneration Research. He continues to see patients in the MND clinic at King’s College Hospital, combining his clinical roles with his research interests.

 

Seminar Synopsis

Amyotrophic lateral sclerosis–frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterized by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Understanding how TDP-43, an RNA binding protein, contributes to neurodegeneration will help direct therapeutic efforts. We created a TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene. TDP-43Q331K mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons. Critically, TDP-43 autoregulation is perturbed, leading to a gain of TDP-43 function and altered splicing of Mapt, another pivotal dementia-associated gene. Furthermore, a simple approach to stratify transcriptomic data by phenotype in differentially affected mutant mice revealed 471 changes linked with improved behavior. These changes included downregulation of two known modifiers of neurodegeneration,Atxn2 and Arid4a, and upregulation of myelination and translation genes. Finally, human cells with the TDP-43Q331K mutation also demonstrate TDP-43 misregulation (unpublished). With one base change in Tardbp/TARDBP, these studies identify TDP-43 misregulation as a pathogenic mechanism that may underpin ALS- FTD and exploit phenotypic heterogeneity to yield candidate suppressors of neurodegenerative disease.

Selected Publications

White MA, Kim E, Duffy A, Adalbert R, Phillips BU, Peters OM, Stephenson J, Yang S, Massenzio F, Lin Z, Andrews S, Segonds-Pichon A, Metterville J, Saksida LM, Mead R, Ribchester RR, Barhomi Y, Serre T, Coleman MP, Fallon J, Bussey TJ, Brown RH Jr, Sreedharan J. TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD Nat Neurosci. 2018 Apr;21(4):552-563

Sreedharan, J., Neukomm, L.J., Brown, R.H., Jr., and Freeman, M.R. (2015). Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2. Curr Biol. 2015 Aug 17;25(16):2130-6

Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008; 319(5870): 1668-72.