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

Nat Commun. 2014 Jun 3;5:3996. doi: 10.1038/ncomms4996.

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 Ca(2+) homeostasis. Finally, we show that overexpression of TDP-43 leads to activation of glycogen synthase kinase-3β (GSK-3β) and that GSK-3β regulates the VAPB-PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Calcium / metabolism
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • Frontotemporal Dementia / metabolism
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • HEK293 Cells
  • Humans
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / metabolism*
  • Protein Tyrosine Phosphatases / metabolism*
  • Vesicular Transport Proteins / metabolism*

Substances

  • DNA-Binding Proteins
  • Membrane Proteins
  • Mitochondrial Proteins
  • TDP-43 protein, human
  • TDP-43 protein, mouse
  • VAPB protein, human
  • VAPB protein, mouse
  • Vesicular Transport Proteins
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3
  • FAM82A2 protein, human
  • PTPIP51 protein, mouse
  • Protein Tyrosine Phosphatases
  • Calcium