{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:00:55Z","timestamp":1788267655391,"version":"build-2803163510"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T00:00:00Z","timestamp":1653609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two major neurodegenerative diseases. FTD is the second most common cause of dementia and ALS is the most common form of motor neuron disease. These diseases are now known to be linked. There are no cures or effective treatments for FTD or ALS and so new targets for therapeutic intervention are required but this is hampered by the large number of physiological processes that are damaged in FTD\/ALS. Many of these damaged functions are now known to be regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by \u201ctethering\u201d proteins that serve to recruit ER to mitochondria. One tether strongly associated with FTD\/ALS involves an interaction between the ER protein VAPB and the mitochondrial protein PTPIP51. Recent studies have shown that ER-mitochondria signaling is damaged in FTD\/ALS and that this involves breaking of the VAPB-PTPIP51 tethers. Correcting disrupted tethering may therefore correct many other downstream damaged features of FTD\/ALS. Here, we review progress on this topic with particular emphasis on targeting of the VAPB-PTPIP51 tethers as a new drug target.<\/jats:p>","DOI":"10.3389\/fcell.2022.915931","type":"journal-article","created":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T06:10:46Z","timestamp":1653631846000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Targeting ER-Mitochondria Signaling as a Therapeutic Target for Frontotemporal Dementia and Related Amyotrophic Lateral Sclerosis"],"prefix":"10.3389","volume":"10","author":[{"given":"Sandra M.","family":"Mart\u00edn-Guerrero","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Markovinovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor M.","family":"M\u00f3rotz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaakir","family":"Salam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Noble","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C. J.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"42","DOI":"10.3389\/fnins.2020.00042","article-title":"The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia","volume":"14","author":"Abramzon","year":"2020","journal-title":"Front. Neurosci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1021\/sb300050j","article-title":"Dimerization-dependent Green and Yellow Fluorescent Proteins","volume":"1","author":"Alford","year":"2012","journal-title":"ACS Synth. Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.bbrc.2006.10.093","article-title":"TDP-43 Is a Component of Ubiquitin-Positive Tau-Negative Inclusions in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis","volume":"351","author":"Arai","year":"2006","journal-title":"Biochem. Biophysical Res. Commun."},{"key":"B4","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1093\/brain\/awv008","article-title":"Dysfunction in Endoplasmic Reticulum-Mitochondria Crosstalk Underlies SIGMAR1 Loss of Function Mediated Motor Neuron Degeneration","volume":"138","author":"Bernard-Marissal","year":"2015","journal-title":"Brain"},{"key":"B5","doi-asserted-by":"publisher","first-page":"5287","DOI":"10.1038\/s41596-021-00614-1","article-title":"Quantification of Organelle Contact Sites by Split-GFP-Based Contact Site Sensors (SPLICS) in Living Cells","volume":"16","author":"Cal\u00ec","year":"2021","journal-title":"Nat. Protoc."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1038\/s41418-017-0033-z","article-title":"SPLICS: a Split Green Fluorescent Protein-Based Contact Site Sensor for Narrow and Wide Heterotypic Organelle Juxtaposition","volume":"25","author":"Cieri","year":"2018","journal-title":"Cell Death Differ."},{"key":"B7","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.ceb.2018.06.003","article-title":"Interacting Organelles","volume":"53","author":"Cohen","year":"2018","journal-title":"Curr. Opin. Cell Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1083\/jcb.200604016","article-title":"Structural and Functional Features and Significance of the Physical Linkage between ER and Mitochondria","volume":"174","author":"Csord\u00e1s","year":"2006","journal-title":"J. Cell Biol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1016\/j.tcb.2018.02.009","article-title":"Endoplasmic Reticulum-Mitochondrial Contactology: Structure and Signaling Functions","volume":"28","author":"Csord\u00e1s","year":"2018","journal-title":"Trends Cell Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1016\/j.stemcr.2020.03.023","article-title":"Impairment of Mitochondrial Calcium Buffering Links Mutations in C9ORF72 and TARDBP in iPS-Derived Motor Neurons from Patients with ALS\/FTD","volume":"14","author":"Dafinca","year":"2020","journal-title":"Stem Cell Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2063","DOI":"10.1002\/stem.2388","article-title":"C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell-Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia","volume":"34","author":"Dafinca","year":"2016","journal-title":"Stem Cells."},{"key":"B12","doi-asserted-by":"publisher","first-page":"56","DOI":"10.3389\/fbioe.2019.00056","article-title":"NanoBRET: The Bright Future of Proximity-Based Assays","volume":"7","author":"Dale","year":"2019","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1093\/hmg\/ddr559","article-title":"VAPB Interacts with the Mitochondrial Protein PTPIP51 to Regulate Calcium Homeostasis","volume":"21","author":"De Vos","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","article-title":"Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS","volume":"72","author":"Dejesus-Hernandez","year":"2011","journal-title":"Neuron."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2413","DOI":"10.1016\/j.bbamcr.2016.03.024","article-title":"Calcium Regulation of Mitochondrial Carriers","volume":"1863","author":"Del Arco","year":"2016","journal-title":"Biochimica Biophysica Acta (BBA) - Mol. Cell Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1038\/nrd.2016.109","article-title":"Twenty Years on: the Impact of Fragments on Drug Discovery","volume":"15","author":"Erlanson","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"B17","doi-asserted-by":"publisher","first-page":"102322","DOI":"10.1016\/j.ceca.2020.102322","article-title":"The Molecular Complexity of the Mitochondrial Calcium Uniporter","volume":"93","author":"Feno","year":"2021","journal-title":"Cell Calcium."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e13549","DOI":"10.1111\/acel.13549","article-title":"Disruption of ER\u2010mitochondria Tethering and Signalling in C9orf72 \u2010associated Amyotrophic Lateral Sclerosis and Frontotemporal Dementia","volume":"21","author":"Gomez\u2010Suaga","year":"2022","journal-title":"Aging Cell."},{"key":"B19","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s40478-019-0688-4","article-title":"The VAPB-PTPIP51 Endoplasmic Reticulum-Mitochondria Tethering Proteins Are Present in Neuronal Synapses and Regulate Synaptic Activity","volume":"7","author":"G\u00f3mez-Suaga","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e47928","DOI":"10.15252\/embr.201947928","article-title":"Metabolic Implications of Organelle-Mitochondria Communication","volume":"20","author":"Gordaliza\u2010Alaguero","year":"2019","journal-title":"EMBO Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"3741","DOI":"10.1093\/hmg\/ddw220","article-title":"Loss-of-function Mutations in theSIGMAR1gene Cause Distal Hereditary Motor Neuropathy by Impairing ER-Mitochondria Tethering and Ca2+signalling","volume":"25","author":"Gregianin","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"7916","DOI":"10.1073\/pnas.1300677110","article-title":"Modulation of the Endoplasmic Reticulum-Mitochondria Interface in Alzheimer's Disease and Related Models","volume":"110","author":"Hedskog","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B23","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1146\/annurev-pathol-012615-044216","article-title":"Dendritic Spine Pathology in Neurodegenerative Diseases","volume":"11","author":"Herms","year":"2016","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1126\/science.aan6009","article-title":"ER-mitochondria Tethering by PDZD8 Regulates Ca2+dynamics in Mammalian Neurons","volume":"358","author":"Hirabayashi","year":"2017","journal-title":"Science."},{"key":"B25","doi-asserted-by":"publisher","first-page":"6175","DOI":"10.1038\/s41598-018-24466-0","article-title":"Visualizing Multiple Inter-organelle Contact Sites Using the Organelle-Targeted Split-GFP System","volume":"8","author":"Kakimoto","year":"2018","journal-title":"Sci. Rep."},{"key":"B26","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1007\/s00401-015-1528-7","article-title":"Mitochondria-associated Membranes as Hubs for Neurodegeneration","volume":"131","author":"Krols","year":"2016","journal-title":"Acta Neuropathol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1126\/science.1254917","article-title":"Poly-dipeptides Encoded by the C9orf72 Repeats Bind Nucleoli, Impede RNA Biogenesis, and Kill Cells","volume":"345","author":"Kwon","year":"2014","journal-title":"Science."},{"key":"B28","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/s41419-017-0022-7","article-title":"Disruption of ER\u2212mitochondria Signalling in Fronto-Temporal Dementia and Related Amyotrophic Lateral Sclerosis","volume":"9","author":"Lau","year":"2018","journal-title":"Cell Death Dis."},{"key":"B29","doi-asserted-by":"publisher","first-page":"118664","DOI":"10.1016\/j.bbamcr.2020.118664","article-title":"Glycogen Synthase Kinase-3 Signaling in Alzheimer's Disease","volume":"1867","author":"Lauretti","year":"2020","journal-title":"Biochimica Biophysica Acta (BBA) - Mol. Cell Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.neuron.2013.07.033","article-title":"Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis","volume":"79","author":"Ling","year":"2013","journal-title":"Neuron."},{"key":"B31","doi-asserted-by":"publisher","first-page":"46","DOI":"10.3389\/fnmol.2014.00046","article-title":"GSK-3\u00ce\u00b2, a Pivotal Kinase in Alzheimer Disease","volume":"7","author":"Llorens-Mart\u00edn","year":"2014","journal-title":"Front. Mol. Neurosci."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.248534","article-title":"Endoplasmic Reticulum-Mitochondria Signaling in Neurons and Neurodegenerative Diseases","volume":"135","author":"Markovinovic","year":"2022","journal-title":"J. Cell Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1126\/science.1256800","article-title":"C9orf72 Repeat Expansions Cause Neurodegeneration in Drosophila through Arginine-Rich Proteins","volume":"345","author":"Mizielinska","year":"2014","journal-title":"Science."},{"key":"B34","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1016\/j.tips.2016.05.008","article-title":"Systematic Targeting of Protein-Protein Interactions","volume":"37","author":"Modell","year":"2016","journal-title":"Trends Pharmacol. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/s12915-021-00979-5","article-title":"Neuronal Cell-Based High-Throughput Screen for Enhancers of Mitochondrial Function Reveals Luteolin as a Modulator of Mitochondria-Endoplasmic Reticulum Coupling","volume":"19","author":"Naia","year":"2021","journal-title":"BMC Biol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1126\/science.1134108","article-title":"Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis","volume":"314","author":"Neumann","year":"2006","journal-title":"Science."},{"key":"B37","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.tins.2016.01.008","article-title":"There's Something Wrong with My MAM; the ER-Mitochondria axis and Neurodegenerative Diseases","volume":"39","author":"Paillusson","year":"2016","journal-title":"Trends Neurosci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/bs.ircmb.2019.11.002","article-title":"The Role of Mitochondria-Associated Membranes in Cellular Homeostasis and Diseases","volume":"350","author":"Perrone","year":"2020","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.neuron.2011.09.010","article-title":"A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD","volume":"72","author":"Renton","year":"2011","journal-title":"Neuron."},{"key":"B40","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.bbrc.2017.06.097","article-title":"Mitochondria-associated Membranes (MAMs): An Emerging Platform Connecting Energy and Immune Sensing to Metabolic Flexibility","volume":"500","author":"Rieusset","year":"2018","journal-title":"Biochem. Biophysical Res. Commun."},{"key":"B41","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1212\/01.wnl.0000172911.39167.b6","article-title":"Prevalence and Patterns of Cognitive Impairment in Sporadic ALS","volume":"65","author":"Ringholz","year":"2005","journal-title":"Neurology."},{"key":"B42","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nrn3430","article-title":"The Changing Scene of Amyotrophic Lateral Sclerosis","volume":"14","author":"Robberecht","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1038\/nrm3440","article-title":"Endoplasmic Reticulum-Mitochondria Contacts: Function of the Junction","volume":"13","author":"Rowland","year":"2012","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"862","DOI":"10.3389\/fnins.2019.00862","article-title":"Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases","volume":"13","author":"Ryskamp","year":"2019","journal-title":"Front. Neurosci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1038\/nmeth947","article-title":"Direct Observation of Individual Endogenous Protein Complexes In Situ by Proximity Ligation","volume":"3","author":"S\u00f6derberg","year":"2006","journal-title":"Nat. Methods."},{"key":"B46","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1007\/s00401-017-1709-7","article-title":"Interactions of Pathological Proteins in Neurodegenerative Diseases","volume":"134","author":"Spires-Jones","year":"2017","journal-title":"Acta Neuropathol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"3996","DOI":"10.1038\/ncomms4996","article-title":"ER-mitochondria Associations Are Regulated by the VAPB-PTPIP51 Interaction and Are Disrupted by ALS\/FTD-associated TDP-43","volume":"5","author":"Stoica","year":"2014","journal-title":"Nat. Commun."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.15252\/embr.201541726","article-title":"ALS\/FTD \u2010associated FUS Activates GSK \u20103\u03b2 to Disrupt the VAPB - PTPIP 51 Interaction and ER -mitochondria Associations","volume":"17","author":"Stoica","year":"2016","journal-title":"EMBO Rep."},{"key":"B49","doi-asserted-by":"publisher","first-page":"2572","DOI":"10.1093\/brain\/awz217","article-title":"Widespread FUS Mislocalization Is a Molecular Hallmark of Amyotrophic Lateral Sclerosis","volume":"142","author":"Tyzack","year":"2019","journal-title":"Brain."},{"key":"B50","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.ejmech.2019.01.084","article-title":"Clinical Candidates Modulating Protein-Protein Interactions: The Fragment-Based Experience","volume":"167","author":"Valenti","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/tra.12230","article-title":"Phospholipid Synthesis and Transport in Mammalian Cells","volume":"16","author":"Vance","year":"2015","journal-title":"Traffic."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.15252\/emmm.201606403","article-title":"Mitochondria\u2010associated Membrane Collapse Is a Common Pathomechanism in SIGMAR 1 \u2010 and SOD 1 \u2010linked ALS","volume":"8","author":"Watanabe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1016\/j.neuron.2014.12.010","article-title":"Antisense Proline-Arginine RAN Dipeptides Linked to C9ORF72-ALS\/FTD Form Toxic Nuclear Aggregates that Initiate In Vitro and In Vivo Neuronal Death","volume":"84","author":"Wen","year":"2014","journal-title":"Neuron."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1212\/01.wnl.0000277422.11236.2c","article-title":"Cognitive Impairment in Familial ALS","volume":"69","author":"Wheaton","year":"2007","journal-title":"Neurology."},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.208686","article-title":"A Novel Fluorescent Reporter Detects Plastic Remodeling of Mitochondria-ER Contact Sites","volume":"131","author":"Yang","year":"2018","journal-title":"J. Cell Sci."},{"key":"B56","doi-asserted-by":"publisher","first-page":"e51323","DOI":"10.15252\/embr.202051323","article-title":"Phospholipid Transfer Function of PTPIP51 at Mitochondria\u2010associated ER Membranes","volume":"22","author":"Yeo","year":"2021","journal-title":"EMBO Rep."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.915931\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T06:10:49Z","timestamp":1653631849000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.915931\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,27]]},"references-count":56,"alternative-id":["10.3389\/fcell.2022.915931"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2022.915931","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,27]]},"article-number":"915931"}}