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TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD.

Authors
 Matthew A. White  ;  Eosu Kim  ;  Amanda Duffy  ;  Robert Adalbert  ;  Benjamin U. Phillips  ;  Owen M. Peters  ;  Jodie Stephenson  ;  Sujeong Yang  ;  Francesca Massenzio  ;  Ziqiang Lin  ;  Simon Andrews  ;  Anne Segonds-Pichon  ;  Jake Metterville  ;  Lisa M. Saksida  ;  Richard Mead  ;  Richard R Ribchester  ;  Youssef Barhomi  ;  Thomas Serre  ;  Michael P. Coleman  ;  Justin R. Fallon  ;  Timothy J. Bussey  ;  Robert H. Brown Jr  ;  Jemeen Sreedharan 
Citation
 Nature Neuroscience, Vol.21(4) : 552-563, 2018 
Journal Title
 Nature Neuroscience 
ISSN
 1097-6256 
Issue Date
2018
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. Here we have 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. With one base change in murine Tardbp, this study identifies TDP-43 misregulation as a pathogenic mechanism that may underpin ALS-FTD and exploits phenotypic heterogeneity to yield candidate suppressors of neurodegenerative disease.
Full Text
http://www.nature.com/articles/s41593-018-0113-5
DOI
10.1038/s41593-018-0113-5
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Psychiatry (정신과학교실) > 1. Journal Papers
Yonsei Authors
김어수(Kim, Eosu) ORCID logo https://orcid.org/0000-0001-9472-9465
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/163245
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