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This signalling involves close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ER\u2013mitochondria \u201ctethering\u201d proteins. A number of studies have shown that mutant genes which cause familial FTD\/ALS disrupt the VAPB-PTPIP51 tethers and that this involves activation of GSK3\u03b2. TDP43 is one such mutant and altered TDP43 metabolism is central to FTD\/ALS pathogenesis. Loss of Sigma-1 receptor function is also seen in FTD\/ALS and there is evidence that Sigma-1 receptor agonists can repair damaged ER\u2013mitochondria signalling. However, the underlying mechanisms are not properly understood. In this study, we show that the reference Sigma-1 receptor agonist PRE-084 stimulates VAPB-PTPIP51 binding and rescues FTD\/ALS mutant TDP43-induced disruption to the VAPB-PTPIP51 interaction and linked ER\u2013mitochondria Ca2+ delivery. We also show that these effects involve inhibition of the kinase GSK3\u03b2, a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that ANAVEX2-73, a further Sigma-1 receptor agonist which is in clinical trials for Alzheimer\u2019s disease, also stimulates VAPB-PTPIP51 binding via GSK3\u03b2 inhibition. Our findings provide novel insights into the mechanisms by which Sigma-1 receptor agonists influence defective ER\u2013mitochondria signalling in FTD\/ALS.<\/jats:p>","DOI":"10.3390\/cells15171536","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T10:59:23Z","timestamp":1787741963000},"page":"1536","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sigma-1 Receptor Stimulation Rescues FTD\/ALS Mutant TDP43-Induced Disruption of the VAPB-PTPIP51 ER\u2013Mitochondria Tethering Proteins via Inhibition of GSK3\u03b2"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6358-3854","authenticated-orcid":false,"given":"Kerry","family":"Blair","sequence":"first","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London WC2R 2LS, UK"},{"name":"Randall Centre for Cell and Molecular Biophysics, King\u2019s College London, London WC2R 2LS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9104-8688","authenticated-orcid":false,"given":"Philippe","family":"Gosset","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London WC2R 2LS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Martinez-Serra","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London WC2R 2LS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4223-7009","authenticated-orcid":false,"given":"G\u00e1bor M.","family":"M\u00f3rotz","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London WC2R 2LS, UK"},{"name":"Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary"},{"name":"Center for Pharmacology and Drug Research & Development, Semmelweis University, H-1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1489-4757","authenticated-orcid":false,"given":"Sandra M.","family":"Mart\u00edn-Guerrero","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London WC2R 2LS, UK"},{"name":"Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Instituto de Parasitolog\u00eda y Biomedicina L\u00f3pez-Neyra, 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2388-8327","authenticated-orcid":false,"given":"Patricia","family":"Gomez-Suaga","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London WC2R 2LS, UK"},{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Gen\u00e9tica, Facultad de Enfermer\u00eda y Terapia Ocupacional, Universidad de Extremadura, 10071 C\u00e1ceres, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Neurodegenerativas-Instituto de Salud Carlos III (CIBER-CIBERNED-ISCIII), 28029 Madrid, Spain"},{"name":"Instituto Universitario de Investigaci\u00f3n Biosanitaria de Extremadura (INUBE), 10071 C\u00e1ceres, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6362-2347","authenticated-orcid":false,"given":"Joseph","family":"Atherton","sequence":"additional","affiliation":[{"name":"Randall Centre for Cell and Molecular Biophysics, King\u2019s College London, London WC2R 2LS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2677-398X","authenticated-orcid":false,"given":"Jacqueline C.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London WC2R 2LS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Noble","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London WC2R 2LS, UK"},{"name":"Department of Clinical and Biomedical Sciences, University of Exeter, Exeter EX4 4QJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C. J.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London WC2R 2LS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1656-3150","authenticated-orcid":false,"given":"Andrea","family":"Markovinovic","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London WC2R 2LS, UK"},{"name":"Department of Anatomy, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Aishwarya, R., Abdullah, C.S., Morshed, M., Remex, N.S., and Bhuiyan, S. (2021). Sigmar1\u2019s Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.705575"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.tips.2019.07.006","article-title":"The Molecular Function of sigma Receptors: Past, Present, and Future","volume":"40","author":"Schmidt","year":"2019","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Couly, S., Yasui, Y., and Su, T.P. (2023). SIGMAR1 Confers Innate Resilience against Neurodegeneration. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24097767"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ryskamp, D.A., Korban, S., Zhemkov, V., Kraskovskaya, N., and Bezprozvanny, I. (2019). Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00862"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Hayashi, T. (2019). The Sigma-1 Receptor in Cellular Stress Signaling. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00733"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1007\/s40263-023-01007-6","article-title":"Targeting Sigma receptors for the treatment of neurodegenerative and neurodevelopmental disorders","volume":"37","author":"Malar","year":"2023","journal-title":"CNS Drugs"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"jcs248534","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":"ref_8","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.tins.2016.01.008","article-title":"There\u2019s something wrong with my MAM; the ER-Mitochondria axis and neurodegenerative diseases","volume":"39","author":"Paillusson","year":"2016","journal-title":"Trends Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6497","DOI":"10.1111\/febs.70184","article-title":"A guide to characterizing the dynamic mitochondria-endoplasmic reticulum contact sites","volume":"292","author":"Diokmetzidou","year":"2025","journal-title":"FEBS J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"102453","DOI":"10.1016\/j.ceca.2021.102453","article-title":"Ca2+ handling at the mitochondria-ER contact sites in neurodegeneration","volume":"98","author":"Lim","year":"2021","journal-title":"Cell Calcium"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.tcb.2018.02.009","article-title":"Endoplasmic Reticular-Mitochondrial Contactology: Structure and Signaling Functions","volume":"28","author":"Weaver","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.cell.2007.08.036","article-title":"Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival","volume":"131","author":"Hayashi","year":"2007","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.15252\/emmm.201606403","article-title":"Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS","volume":"8","author":"Watanabe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","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":"Azzedine","year":"2015","journal-title":"Brain"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3741","DOI":"10.1093\/hmg\/ddw220","article-title":"Loss-of-function mutations in the SIGMAR1 gene 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":"ref_16","doi-asserted-by":"crossref","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":"ref_17","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1093\/hmg\/ddr559","article-title":"VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis","volume":"21","author":"Stoica","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/s41586-023-06956-y","article-title":"Motion of VAPB molecules reveals ER-mitochondria contact site subdomains","volume":"626","author":"Obara","year":"2024","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s40478-025-01964-7","article-title":"Structural and functional studies of the VAPB-PTPIP51 ER-mitochondria tethering proteins in neurodegenerative diseases","volume":"13","author":"Blair","year":"2025","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e202112107","DOI":"10.1083\/jcb.202112107","article-title":"ORP5 and ORP8 orchestrate lipid droplet biogenesis and maintenance at ER-mitochondria contact sites","volume":"221","author":"Guyard","year":"2022","journal-title":"J. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"14097","DOI":"10.1074\/jbc.M500147200","article-title":"A highly conserved binding site in VAP for the FFAT motif of lipid binding proteins","volume":"280","author":"Loewen","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e51323","DOI":"10.15252\/embr.202051323","article-title":"Phospholipid transfer function of PTPIP51 at mitochondria-associated ER membranes","volume":"22","author":"Yeo","year":"2021","journal-title":"EMBO Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.cub.2016.12.038","article-title":"The ER-mitochondria tethering complex VAPB-PTPIP51 regulates autophagy","volume":"27","author":"Paillusson","year":"2017","journal-title":"Curr. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","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":"Glennon","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1002\/ana.22534","article-title":"A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis","volume":"70","author":"Bohlega","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1002\/ana.22274","article-title":"Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease","volume":"68","author":"Luty","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1212\/WNL.0000000000001680","article-title":"A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy","volume":"84","author":"Li","year":"2015","journal-title":"Neurology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2329048x16669912","DOI":"10.1177\/2329048X16669912","article-title":"Further Validation of the SIGMAR1 c.151+1G>T Mutation as Cause of Distal Hereditary Motor Neuropathy","volume":"3","author":"Lee","year":"2016","journal-title":"Child Neurol. Open"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1136\/jmedgenet-2019-106108","article-title":"Distal hereditary motor neuronopathy of the Jerash type is caused by a novel SIGMAR1 c.500A>T missense mutation","volume":"57","author":"Ververis","year":"2020","journal-title":"J. Med. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","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":"ref_31","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1126\/science.1154584","article-title":"TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis","volume":"319","author":"Sreedharan","year":"2008","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","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":"ref_33","doi-asserted-by":"crossref","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. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/s00401-009-0571-7","article-title":"TARDBP 3\u2019-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy","volume":"118","author":"Gitcho","year":"2009","journal-title":"Acta Neuropathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/ana.21612","article-title":"TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration","volume":"69","author":"Benajiba","year":"2009","journal-title":"Ann. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1002\/mds.22697","article-title":"TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea","volume":"24","author":"Kovacs","year":"2009","journal-title":"Mov. Disord."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"E974","DOI":"10.1002\/humu.21100","article-title":"Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease","volume":"30","author":"Borroni","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_38","first-page":"86","article-title":"TDP-43 proteinopathies: A new wave of neurodegenerative diseases","volume":"92","author":"Orie","year":"2020","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_39","first-page":"e635","article-title":"The multistep hypothesis of ALS revisited: The role of genetic mutations","volume":"91","author":"Mazzini","year":"2018","journal-title":"Neurology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s00401-017-1709-7","article-title":"Interactions of pathological proteins in neurodegenerative diseases","volume":"134","author":"Attems","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s40478-024-01742-x","article-title":"Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD\/ALS mutant TDP43 linked Ca2+ and synaptic defects","volume":"12","author":"Markovinovic","year":"2024","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.15252\/embr.201541726","article-title":"ALS\/FTD-associated FUS activates GSK-3beta to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations","volume":"17","author":"Stoica","year":"2016","journal-title":"EMBO Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4947","DOI":"10.1093\/hmg\/ddr432","article-title":"Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation","volume":"20","author":"Ambegaokar","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e13549","DOI":"10.1111\/acel.13549","article-title":"Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia","volume":"21","author":"Markovinovic","year":"2022","journal-title":"Aging Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1016\/j.cub.2015.06.045","article-title":"Age-Dependent TDP-43-mediated motor neuron degeneration requires GSK3, hat-trick, and xmas-2","volume":"25","author":"Sreedharan","year":"2015","journal-title":"Curr. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e57499","DOI":"10.15252\/embr.202357499","article-title":"ER-mitochondria contacts and cholesterol metabolism are disrupted by disease-associated tau protein","volume":"24","author":"Szabo","year":"2023","journal-title":"EMBO Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1007\/s12035-026-05675-5","article-title":"Inhibiting Glycogen Synthase Kinase 3 Suppresses TDP-43-Mediated Neurotoxicity in a Caspase-Dependent Manner","volume":"63","author":"White","year":"2026","journal-title":"Mol. Neurobiol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Peggion, C., Massimino, M.L., Bonadio, R.S., Lia, F., Lopreiato, R., Cagnin, S., Cal\u00ec, T., and Bertoli, A. (2021). Regulation of Endoplasmic Reticulum-Mitochondria Tethering and Ca2+ Fluxes by TDP-43 via GSK3\u03b2. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111853"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1046\/j.1460-9568.2003.02950.x","article-title":"Generation and phenotypic analysis of sigma receptor type I (sigma 1) knockout mice","volume":"18","author":"Langa","year":"2003","journal-title":"Eur. J. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.neuroscience.2010.02.022","article-title":"The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons. An anatomical and behavioral study","volume":"167","author":"Mavlyutov","year":"2010","journal-title":"Neuroscience"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.neulet.2013.12.005","article-title":"SA4503, a sigma-1 receptor agonist, suppresses motor neuron damage in in vitro and in vivo amyotrophic lateral sclerosis models","volume":"559","author":"Ono","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1007\/s13311-012-0140-y","article-title":"Sigma-1R agonist improves motor function and motoneuron survival in ALS mice","volume":"9","author":"Mancuso","year":"2012","journal-title":"Neurotherapeutics"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s40035-025-00527-z","article-title":"Positive modulation of sigma-1 receptor: A new weapon to mitigate disease progression in amyotrophic lateral sclerosis","volume":"14","author":"Mourier","year":"2025","journal-title":"Transl. Neurodegener."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1111\/bph.15224","article-title":"Sigma 1 receptor as a therapeutic target for amyotrophic lateral sclerosis","volume":"178","author":"Vela","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1186\/s40478-019-0857-5","article-title":"Kinesin light chain-1 serine-460 phosphorylation is altered in Alzheimer\u2019s disease and regulates axonal transport and processing of the amyloid precursor protein","volume":"7","author":"Glennon","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s00401-017-1704-z","article-title":"alpha-Synuclein binds to the ER-mitochondria tethering protein VAPB to disrupt Ca2+ homeostasis and mitochondrial ATP production","volume":"134","author":"Paillusson","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"M\u00f3rotz, G.M., Mart\u00edn-Guerrero, S.M., Markovinovic, A., Paillusson, S., Russell, M.R.G., Machado, P.M.P., Fleck, R.A., Noble, W., and Miller, C.C. (2022). The PTPIP51 coiled-coil domain is important in VAPB binding, formation of ER-mitochondria contacts and IP3 receptor delivery of Ca2+ to mitochondria. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.920947"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1093\/hmg\/dds011","article-title":"Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria","volume":"21","author":"Vagnoni","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s40478-019-0715-5","article-title":"LMTK2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5\/p35 and LMTK2 levels are reduced in Alzheimer\u2019s disease brains","volume":"7","author":"Glennon","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4646","DOI":"10.1093\/hmg\/ddt313","article-title":"Loss of c-Jun N-terminal kinase-interacting protein-1 does not affect axonal transport of the amyloid precursor protein or Abeta production","volume":"22","author":"Vagnoni","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1083\/jcb.200303138","article-title":"Neurofilament heavy chain side-arm phosphorylation regulates axonal transport of neurofilaments","volume":"161","author":"Ackerley","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1242\/jcs.075168","article-title":"Phosphorylation of kinesin light chain-1 at serine-460 modulates binding and trafficking of calsyntenin-1","volume":"124","author":"Vagnoni","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1093\/hmg\/dds109","article-title":"Calsyntenin-1 mediates axonal transport of the amyloid precursor protein and regulates Abeta production","volume":"21","author":"Vagnoni","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"105803","DOI":"10.1016\/j.biocel.2020.105803","article-title":"PRE-084 as a tool to uncover potential therapeutic applications for selective sigma-1 receptor activation","volume":"126","author":"Motawe","year":"2020","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.nbd.2013.10.010","article-title":"Neuroprotective effects of the Sigma-1 receptor (S1R) agonist PRE-084, in a mouse model of motor neuron disease not linked to SOD1 mutation","volume":"62","author":"Peviani","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Gaja-Capdevila, N., Hern\u00e1ndez, N., Navarro, X., and Herrando-Grabulosa, M. (2021). Sigma-1 Receptor is a Pharmacological Target to Promote Neuroprotection in the SOD1(G93A) ALS Mice. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.780588"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"102542","DOI":"10.1016\/j.redox.2022.102542","article-title":"Sigma-1 receptor agonist PRE-084 confers protection against TAR DNA-binding protein-43 toxicity through NRF2 signalling","volume":"58","author":"Lasbleiz","year":"2022","journal-title":"Redox Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.neuropharm.2010.05.014","article-title":"The \u03c3 1 receptor agonist 4-PPBP elicits ERK1\/2 phosphorylation in primary neurons: A possible mechanism of neuroprotective action","volume":"59","author":"Tan","year":"2010","journal-title":"Neuropharmacology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.neuroscience.2009.03.067","article-title":"Selective sigma receptor agonist 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE084) promotes neuroprotection and neurite elongation through protein kinase C (PKC) signaling on motoneurons","volume":"162","author":"Navarro","year":"2009","journal-title":"Neuroscience"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Du, M., Jiang, T., He, S., Cheng, B., Zhang, X., Li, L., Yang, L., Gao, W., Li, Y., and Wang, Q. (2023). Sigma-1 Receptor as a Protective Factor for Diabetes-Associated Cognitive Dysfunction via Regulating Astrocytic Endoplasmic Reticulum-Mitochondrion Contact and Endoplasmic Reticulum Stress. Cells, 12.","DOI":"10.3390\/cells12010197"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Kaidanovich-Beilin, O., and Woodgett, J.R. (2011). GSK-3: Functional insights from cell biology and animal models. Front. Mol. Neurosci., 4.","DOI":"10.3389\/fnmol.2011.00040"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Mart\u00edn-Guerrero, S.M., Markovinovic, A., M\u00f3rotz, G.M., Salam, S., Noble, W., and Miller, C.C.J. (2022). Targeting ER-Mitochondria Signaling as a Therapeutic Target for Frontotemporal Dementia and Related Amyotrophic Lateral Sclerosis. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.915931"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Choi, H.-J., Cha, S.J., Lee, J.-W., Kim, H.-J., and Kim, K. (2020). Recent Advances on the Role of GSK3\u03b2 in the Pathogenesis of Amyotrophic Lateral Sclerosis. Brain Sci., 10.","DOI":"10.3390\/brainsci10100675"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Lahmy, V., Long, R., Morin, D., Villard, V., and Maurice, T. (2015). Mitochondrial protection by the mixed muscarinic\/sigma1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Abeta25-35 peptide-injected mice, a nontransgenic Alzheimer\u2019s disease model. Front. Cell Neurosci., 8.","DOI":"10.3389\/fncel.2014.00463"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1038\/npp.2013.70","article-title":"Blockade of Tau hyperphosphorylation and A\u03b21\u201342 generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and sigma(1) receptor agonist, in a nontransgenic mouse model of Alzheimer\u2019s disease","volume":"38","author":"Lahmy","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.bbr.2015.09.020","article-title":"Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments","volume":"296","author":"Maurice","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_77","first-page":"e12013","article-title":"A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer\u2019s disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study","volume":"6","author":"Hampel","year":"2020","journal-title":"Alzheimers Dement."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"100016","DOI":"10.1016\/j.tjpad.2024.100016","article-title":"Blarcamesine for the treatment of Early Alzheimer\u2019s Disease: Results from the ANAVEX2-73-AD-004 Phase IIB\/III trial","volume":"12","author":"Macfarlane","year":"2025","journal-title":"J. Prev. Alzheimers Dis."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Christ, M.G., Huesmann, H., Nagel, H., Kern, A., and Behl, C. (2019). Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo. Cells, 8.","DOI":"10.3390\/cells8030211"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e2315347120","DOI":"10.1073\/pnas.2315347120","article-title":"Mitochondria-associated membrane collapse impairs TBK1-mediated proteostatic stress response in ALS","volume":"120","author":"Watanabe","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"106031","DOI":"10.1016\/j.nbd.2023.106031","article-title":"Sigma-1 receptor maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation at the mitochondria-associated membrane in amyotrophic lateral sclerosis","volume":"179","author":"Watanabe","year":"2023","journal-title":"Neurobiol. Dis."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1021\/acsptsci.4c00564","article-title":"Sigma 1 Receptor and Its Pivotal Role in Neurological Disorders","volume":"8","author":"Shokr","year":"2025","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41467-024-51578-1","article-title":"Altered mitochondria-associated ER membrane (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS)","volume":"16","author":"Larrea","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e21688","DOI":"10.1096\/fj.202100137R","article-title":"Novel reporters of mitochondria-associated membranes (MAM), MAMtrackers, demonstrate MAM disruption as a common pathological feature in amyotrophic lateral sclerosis","volume":"35","author":"Sakai","year":"2021","journal-title":"FASEB J."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.expneurol.2013.03.027","article-title":"Overexpression of human mutated G93A SOD1 changes dynamics of the ER mitochondria calcium cycle specifically in mouse embryonic motor neurons","volume":"247","author":"Prell","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.neuroscience.2017.07.012","article-title":"Sigma 1 receptor activation modifies intracellular calcium exchange in the G93AhSOD1 ALS model","volume":"359","author":"Malci","year":"2017","journal-title":"Neuroscience"},{"key":"ref_87","doi-asserted-by":"crossref","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":"ref_88","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1007\/s00401-022-02494-5","article-title":"PolyGA targets the ER stress-adaptive response by impairing GRP75 function at the MAM in C9ORF72-ALS\/FTD","volume":"144","author":"Pilotto","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"111226","DOI":"10.1016\/j.brainresbull.2025.111226","article-title":"Pharmacological modulation of Sigma-1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the AKT\/GSK-3\u03b2\/NF-\u03baB pathway","volume":"221","author":"An","year":"2025","journal-title":"Brain Res. Bull."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"105020","DOI":"10.1016\/j.nbd.2020.105020","article-title":"Disruption of endoplasmic reticulum-mitochondria tethering proteins in post-mortem Alzheimer\u2019s disease brain","volume":"143","author":"Lau","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/S0960-9822(00)00246-3","article-title":"Alzheimer\u2019s disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells","volume":"4","author":"Lovestone","year":"1994","journal-title":"Curr. Biol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e14818","DOI":"10.1111\/cns.14818","article-title":"GSK3: A potential target and pending issues for treatment of Alzheimer\u2019s disease","volume":"30","author":"Zhao","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Godoy-Corchuelo, J.M., Fern\u00e1ndez-Beltr\u00e1n, L.C., Ali, Z., Gil-Moreno, M.J., L\u00f3pez-Carbonero, J.I., Guerrero-Sola, A., Larrad-Sainz, A., Matias-Guiu, J., Matias-Guiu, J.A., and Cunningham, T.J. (2022). Lipid Metabolic Alterations in the ALS-FTD Spectrum of Disorders. Biomedicines, 10.","DOI":"10.3390\/biomedicines10051105"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1002\/1873-3468.14893","article-title":"Emerging functions of the mitochondria-ER-lipid droplet three-way junction in coordinating lipid transfer, metabolism, and storage in cells","volume":"598","author":"Giordano","year":"2024","journal-title":"FEBS Lett."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/17\/1536\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T04:24:34Z","timestamp":1787891074000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/17\/1536"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,26]]},"references-count":94,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cells15171536"],"URL":"https:\/\/doi.org\/10.3390\/cells15171536","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,26]]}}}