ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43
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AbstractMitochondria 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-3β (GSK-3β) and that GSK-3β regulates the VAPB-PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43. © 2014 Macmillan Publishers Limited. All rights reserved.
All Author(s) ListStoica R., De Vos K.J., Paillusson S., Mueller S., Sancho R.M., Lau K.-F., Vizcay-Barrena G., Lin W.-L., Xu Y.-F., Lewis J., Dickson D.W., Petrucelli L., Mitchell J.C., Shaw C.E., Miller C.C.J.
Journal nameNature Communications
Year2014
Month6
Day3
Volume Number5
PublisherNature Publishing Group
Place of PublicationUnited Kingdom
ISSN2041-1723
LanguagesEnglish-United Kingdom

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