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, Sébastien 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 and Christopher C. J. Miller ()
Additional contact information
Radu Stoica: Institute of Psychiatry, Kings College London
Kurt J. De Vos: Institute of Psychiatry, Kings College London
Sébastien Paillusson: Institute of Psychiatry, Kings College London
Sarah Mueller: Institute of Psychiatry, Kings College London
Rosa M. Sancho: Institute of Psychiatry, Kings College London
Kwok-Fai Lau: Institute of Psychiatry, Kings College London
Gema Vizcay-Barrena: Centre for Ultrastructural Imaging, King’s College London
Wen-Lang Lin: Mayo Clinic
Ya-Fei Xu: Mayo Clinic
Jada Lewis: Mayo Clinic
Dennis W. Dickson: Mayo Clinic
Leonard Petrucelli: Mayo Clinic
Jacqueline C. Mitchell: Clinical Neurosciences, Institute of Psychiatry, Kings College London
Christopher E. Shaw: Clinical Neurosciences, Institute of Psychiatry, Kings College London
Christopher C. J. Miller: Institute of Psychiatry, Kings College London

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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-3β (GSK-3β) and that GSK-3β regulates the VAPB–PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43.

Date: 2014
References: Add references at CitEc
Citations: View citations in EconPapers (5)

Downloads: (external link)
https://www.nature.com/articles/ncomms4996 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4996

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms4996

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().