ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43

Radu Stoica, Kurt J. De Vos, Sebastien Paillusson, Sarah Mueller, Rosa M. Sancho, Kwok-Fai Lau, Gema Vizcay-Barrena, Wen-Lang Lin, Ya-Fei Xu, Jada Lewis, Dennis W. Dickson, Leonard Petrucelli, Jacqueline C. Mitchell, Christopher E. Shaw, Christopher C. J. Miller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

438 Citations (Scopus)
195 Downloads (Pure)

Abstract

Mitochondria and the endoplasmic reticulum (ER) form tight structural associations and these facilitate a number of cellular functions. However, the mechanisms by which regions of the ER become tethered to mitochondria are not properly known. Understanding these mechanisms is not just important for comprehending fundamental physiological processes but also for understanding pathogenic processes in some disease states. In particular, disruption to ER-mitochondria associations is linked to some neurodegenerative diseases. Here we show that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER-mitochondria associations. Moreover, we demonstrate that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER-mitochondria interactions and that this is associated with disruption to the VAPB-PTPIP51 interaction and cellular Ca2+ homeostasis. Finally, we show that overexpression of TDP-43 leads to activation of glycogen synthase kinase-3 beta (GSK-3 beta) and that GSK-3 beta regulates the VAPB-PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43.

Original languageEnglish
Article number3996
Pages (from-to)1-12
Number of pages12
JournalNature Communications
Volume5
Issue number1
Early online date3 Jun 2014
DOIs
Publication statusPublished - 3 Jun 2014

Keywords

  • AMYOTROPHIC-LATERAL-SCLEROSIS
  • FRONTOTEMPORAL LOBAR DEGENERATION
  • ENDOPLASMIC-RETICULUM
  • TRANSGENIC MICE
  • CALCIUM HOMEOSTASIS
  • ALZHEIMERS-DISEASE
  • AXONAL-TRANSPORT
  • ALPHA-SYNUCLEIN
  • PROTEIN TDP-43
  • MOTOR-NEURONS

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