Mutations in TGM6 induce the unfolded protein response in SCA35

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...

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Bibliographic Details
Published in:	Human molecular genetics 2017-10, Vol.26 (19), p.3749-3762
Main Authors:	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, Basso, Manuela
Format:	Article
Language:	eng
Subjects:	Animals Animals, Genetically Modified Cell Line Chlorocebus aethiops COS Cells Drosophila melanogaster Endoplasmic Reticulum - metabolism Endoplasmic Reticulum Stress - genetics Female HEK293 Cells Humans Male Mice, Inbred C57BL Mutation Neurons - enzymology Neurons - metabolism Neurons - pathology Spinocerebellar Ataxias - enzymology Spinocerebellar Ataxias - genetics Spinocerebellar Ataxias - metabolism Spinocerebellar Ataxias - pathology Transglutaminases - genetics Transglutaminases - metabolism Unfolded Protein Response - genetics
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Summary:	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 the seven new TG6 mutants and the five TG6 mutants previously linked to SCA35. We found that the wild-type (TG6-WT) protein 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 stress response. Mutations associated with activation of the UPR caused death of primary neurons and reduced the survival of novel Drosophila 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.
ISSN:	0964-6906 1460-2083