title: ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43.
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.
authors.affiliation: 1] Department of Neuroscience, Institute of Psychiatry, Kings College London, London SE5 8AF, UK [2] Clinical Neurosciences, Institute of Psychiatry, Kings College London, London SE5 8AF, UK [3].
authors.forename: Radu
authors.initials: R
authors.lastname: Stoica
authors.affiliation: 1] Department of Neuroscience, Institute of Psychiatry, Kings College London, London SE5 8AF, UK [2] Clinical Neurosciences, Institute of Psychiatry, Kings College London, London SE5 8AF, UK [3] [4].
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: De Vos
authors.affiliation: 1] Department of Neuroscience, Institute of Psychiatry, Kings College London, London SE5 8AF, UK [2] Clinical Neurosciences, Institute of Psychiatry, Kings College London, London SE5 8AF, UK.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Paillusson
authors.affiliation: 1] Department of Neuroscience, Institute of Psychiatry, Kings College London, London SE5 8AF, UK [2] Clinical Neurosciences, Institute of Psychiatry, Kings College London, London SE5 8AF, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mueller
authors.affiliation: 1] Department of Neuroscience, Institute of Psychiatry, Kings College London, London SE5 8AF, UK [2] Clinical Neurosciences, Institute of Psychiatry, Kings College London, London SE5 8AF, UK [3].
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Sancho
authors.affiliation: 1] Department of Neuroscience, Institute of Psychiatry, Kings College London, London SE5 8AF, UK [2].
authors.forename: Kwok-Fai
authors.initials: KF
authors.lastname: Lau
authors.affiliation: Centre for Ultrastructural Imaging, King's College London, London SE5 8AF, UK.
authors.forename: Gema
authors.initials: G
authors.lastname: Vizcay-Barrena
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Ya-Fei
authors.initials: YF
authors.lastname: Xu
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Jada
authors.initials: J
authors.lastname: Lewis
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.affiliation: Clinical Neurosciences, Institute of Psychiatry, Kings College London, London SE5 8AF, UK.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Mitchell
authors.affiliation: Clinical Neurosciences, Institute of Psychiatry, Kings College London, London SE5 8AF, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.affiliation: 1] Department of Neuroscience, Institute of Psychiatry, Kings College London, London SE5 8AF, UK [2] Clinical Neurosciences, Institute of Psychiatry, Kings College London, London SE5 8AF, UK.
authors.forename: Christopher C J
authors.initials: CC
authors.lastname: Miller
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D057180:Frontotemporal Dementia / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D002118:Calcium; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017027:Protein Tyrosine Phosphatases; D033921:Vesicular Transport Proteins; C000598624:TARDBP protein, human; C578077:Tardbp protein, mouse; C496748:VAPB protein, human; C529892:VAPB protein, mouse; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse; C534801:PTPIP51 protein, mouse; C515449:RMDN3 protein, human