title: ALS/FTD-associated FUS activates GSK-3β to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations.
abstract: Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is facilitated by close physical associations between the two organelles that are mediated by binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51, which act as molecular scaffolds to tether the two organelles. Here, we show that FUS disrupts the VAPB-PTPIP51 interaction and ER-mitochondria associations. These disruptions are accompanied by perturbation of Ca(2+) uptake by mitochondria following its release from ER stores, which is a physiological read-out of ER-mitochondria contacts. We also demonstrate that mitochondrial ATP production is impaired in FUS-expressing cells; mitochondrial ATP production is linked to Ca(2+) levels. Finally, we demonstrate that the FUS-induced reductions to ER-mitochondria associations and are linked to activation of glycogen synthase kinase-3β (GSK-3β), a kinase already strongly associated with ALS/FTD.
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
authors.forename: Radu
authors.initials: R
authors.lastname: Stoica
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Paillusson
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gomez-Suaga
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Mitchell
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
authors.forename: Dawn Hw
authors.initials: DH
authors.lastname: Lau
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
authors.forename: Emma H
authors.initials: EH
authors.lastname: Gray
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Sancho
authors.affiliation: Centre for Ultrastructural Imaging, King's College London, London, UK.
authors.forename: Gema
authors.initials: G
authors.lastname: Vizcay-Barrena
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
authors.forename: Kurt J
authors.identifier: 0000-0003-2161-6309
authors.initials: KJ
authors.lastname: De Vos
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
authors.forename: Diane P
authors.initials: DP
authors.lastname: Hanger
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: Noble
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK chris.miller@kcl.ac.uk.
authors.forename: Christopher Cj
authors.identifier: 0000-0002-5130-1845
authors.initials: CC
authors.lastname: Miller
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D004789:Enzyme Activation; D057180:Frontotemporal Dementia / Q000378:metabolism*; D015870:Gene Expression; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D034702:RNA-Binding Protein FUS; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins; D000255:Adenosine Triphosphate; D000071679:Glycogen Synthase Kinase 3 beta; D017027:Protein Tyrosine Phosphatases; C515449:RMDN3 protein, human; D002118:Calcium
keywords: amyotrophic lateral sclerosis; frontotemporal dementia; glycogen synthase kinase‐3β; protein tyrosine phosphatase interacting protein 51; vesicle‐associated membrane protein‐associated protein B