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Mutations in TGM6 induce the unfolded protein response in SCA35

Tripathy, Debasmita, Vignoli, Beatrice, Ramesh, Nandini, Polanco, Maria Jose, Coutelier, Marie, Stephen, Christopher D, Canossa, Marco, Monin, Marie-Lorraine, Aeschlimann, Pascale, Turberville, Shannon, Aeschlimann, Daniel, Schmahmann, Jeremy D, Hadjivassiliou, Marios, Durr, Alexandra, Pandey, Udai B, Pennuto, Maria and Basso, Manuela 2017. Mutations in TGM6 induce the unfolded protein response in SCA35. Human Molecular Genetics 26 (19) , pp. 3749-3762. 10.1093/hmg/ddx259

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Abstract

Spinocerebellar ataxia type 35 (SCA35) is a rare autosomal-dominant neurodegenerative disease caused by mutations in the TGM6 gene, which codes for transglutaminase 6 (TG6). Mutations in TG6 induce cerebellar degeneration by an unknown mechanism. We identified seven patients bearing new mutations in TGM6. To gain insights into the molecular basis of mutant TG6-induced neurotoxicity, we analyzed all of the seven new TG6 mutants and the five TG6 mutants previously linked to SCA35. We found that wild-type (TG6-WT) mainly localized to the nucleus and perinuclear area, whereas five TG6 mutations showed nuclear depletion, increased accumulation in the perinuclear area, insolubility and loss of enzymatic function. Aberrant accumulation of these TG6 mutants in the perinuclear area led to activation of the unfolded protein response (UPR), suggesting that specific TG6 mutants elicit an endoplasmic reticulum (ER) stress response. Mutations associated with activation of the UPR caused death of primary neurons and reduced the survival of novel D. melanogaster models of SCA35. These results indicate that mutations differently impacting on TG6 function cause neuronal dysfunction and death through diverse mechanisms and highlight the UPR as a potential therapeutic target for patient treatment.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords: SCA35, Transglutaminase 6, UPR, ER stress
Publisher: Oxford University Press
ISSN: 0964-6906
Funders: Ryder Briggs Trust Sheffield UK, Zedira, Darmstadt Germany, Cardiff University, University of Trento, Alzheimer Trento Onlus / Legato Baldrachi, Telethon Italy
Date of First Compliant Deposit: 6 July 2017
Date of Acceptance: 30 June 2017
Last Modified: 27 Jan 2019 23:18
URI: http://orca.cf.ac.uk/id/eprint/101959

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