Abstract: 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 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 new 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 Finally, human cells with the TDP-43Q331K mutation demonstrate TDP-43 misregulation (unpublished).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.

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 moved his lab to 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.