Mutations in TGM6 induce the unfolded protein response in SCA35

  • Hum Mol Genet. 2017 Oct 1;26(19):3749-3762. doi: 10.1093/hmg/ddx259.
Debasmita Tripathy  1 ,  Beatrice Vignoli  2 ,  Nandini Ramesh  3  4 ,  Maria Jose Polanco  5 ,  Marie Coutelier  6 ,  Christopher D Stephen  7 ,  Marco Canossa  2 ,  Marie-Lorraine Monin  6 ,  Pascale Aeschlimann  8 ,  Shannon Turberville  8 ,  Daniel Aeschlimann  8 ,  Jeremy D Schmahmann  7 ,  Marios Hadjivassiliou  9 ,  Alexandra Durr  6 ,  Udai B Pandey  3 ,  Maria Pennuto  5 ,  Manuela Basso  1
Affiliations
  • 1. Laboratory of Transcriptional Neurobiology, Centre for Integrative Biology (CIBIO), University of Trento, Trento (TN), Italy.
  • 2. Laboratory of Neural Stem Cells and Neurogenesis, Centre for Integrative Biology (CIBIO), University of Trento, Trento (TN), Italy.
  • 3. Division of Child Neurology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • 4. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
  • 5. Dulbecco Telethon Institute Lab of Neurodegenerative Diseases, Centre for Integrative Biology (CIBIO), University of Trento, Trento (TN), Italy.
  • 6. INSERM U 1127, Centre National de la Recherche Scientifique UMR 7225, UMRS 1127, Université Pierre et Marie Curie (Paris 06), Sorbonne Universités, Institut du Cerveau et de la Moelle Epinière, 75013 Paris, France.
  • 7. Ataxia Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 8. Matrix Biology & Tissue Repair Research Unit, College of Biomedical and Life Sciences, School of Dentistry, Cardiff University, Cardiff, UK.
  • 9. Academic Department of Neurosciences, Royal Hallamshire Hospital, University of Sheffield, Sheffield, UK.
PMID: 28934387 DOI: 10.1093/hmg/ddx259
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 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.