TY - JOUR
T1 - ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43
AU - Stoica, Radu
AU - De Vos, Kurt J.
AU - Paillusson, Sébastien
AU - Mueller, Sarah
AU - Sancho, Rosa M.
AU - Lau, Kwok Fai
AU - Vizcay-Barrena, Gema
AU - Lin, Wen Lang
AU - Xu, Ya Fei
AU - Lewis, Jada
AU - Dickson, Dennis W.
AU - Petrucelli, Leonard
AU - Mitchell, Jacqueline C.
AU - Shaw, Christopher E.
AU - Miller, Christopher C.J.
N1 - Funding Information:
This work was supported by grants from the MRC, Wellcome Trust, Alzheimer’s Research UK, the Motor Neurone Disease Association and European Union.
PY - 2014/6/3
Y1 - 2014/6/3
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms4996
DO - 10.1038/ncomms4996
M3 - Article
C2 - 24893131
AN - SCOPUS:84901925681
SN - 2041-1723
VL - 5
JO - Nature communications
JF - Nature communications
M1 - 3996
ER -