{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T09:50:52Z","timestamp":1791366652775,"version":"4.3.1"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Neurosci"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Disrupted axonal transport and astrocyte dysfunction are implicated in amyotrophic lateral sclerosis (ALS). Here we show these processes are linked\u2014human-induced pluripotent stem-cell-derived astrocytes carrying the\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    mutation disrupt mitochondrial axonal transport and mitochondrial function in cocultured motor neurons (MNs). Conversely, isogenic gene-corrected astrocytes or boosting astrocytic mitochondrial bioenergetics rescue axonal mitochondrial transport deficits in C9ORF72 MNs. Our results delineate a non-cell-autonomous role for astrocytes in regulating mitochondrial transport along axons in ALS models.\n                  <\/jats:p>","DOI":"10.1038\/s41593-026-02464-0","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T09:02:39Z","timestamp":1791363759000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Astrocytes regulate axonal mitochondrial transport deficits in C9ORF72 amyotrophic lateral sclerosis motor neurons"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6074-5050","authenticated-orcid":false,"given":"Maria","family":"Stavrou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ine Br\u00edd","family":"Heffernan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roderick N.","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6269-6408","authenticated-orcid":false,"given":"Owen","family":"Dando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3129-1168","authenticated-orcid":false,"given":"Zoeb","family":"Jiwaji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Burr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyoti","family":"Nanda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4250-7216","authenticated-orcid":false,"given":"David","family":"Villarroel-Campos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alya","family":"Masoud Abdelhafid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Cholewa-Waclaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0413-2820","authenticated-orcid":false,"given":"Daniel","family":"Soong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Story","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4319-8745","authenticated-orcid":false,"given":"Giampietro","family":"Schiavo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7629-5314","authenticated-orcid":false,"given":"Giles E.","family":"Hardingham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6827-1593","authenticated-orcid":false,"given":"Siddharthan","family":"Chandran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7299-0910","authenticated-orcid":false,"given":"Bhuvaneish T.","family":"Selvaraj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"2464_CR1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2020.556175","volume":"13","author":"L Guillaud","year":"2020","unstructured":"Guillaud, L. et al. Anterograde axonal transport in neuronal homeostasis and disease. Front. Mol. Neurosci. 13, 556175 https:\/\/doi.org\/10.3389\/fnmol.2020.556175 (2020).","journal-title":"Front. Mol. Neurosci."},{"key":"2464_CR2","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1016\/j.cmet.2020.02.002","volume":"31","author":"Q Han","year":"2020","unstructured":"Han, Q. et al. Restoring cellular energetics promotes axonal regeneration and functional recovery after spinal cord injury. Cell Metab. 31, 623\u2013641 https:\/\/doi.org\/10.1016\/j.cmet.2020.02.002 (2020).","journal-title":"Cell Metab."},{"key":"2464_CR3","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1038\/s41582-019-0257-2","volume":"15","author":"JN Sleigh","year":"2019","unstructured":"Sleigh, J. N. et al. Axonal transport and neurological disease. Nat. Rev. Neurol. 15, 691\u2013703 https:\/\/doi.org\/10.1038\/s41582-019-0257-2 (2019).","journal-title":"Nat. Rev. Neurol."},{"key":"2464_CR4","doi-asserted-by":"publisher","first-page":"2063","DOI":"10.1002\/stem.2388","volume":"34","author":"R Dafinca","year":"2016","unstructured":"Dafinca, R. et al. 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. Stem Cells 34, 2063\u20132078 https:\/\/doi.org\/10.1002\/stem.2388 (2016).","journal-title":"Stem Cells"},{"key":"2464_CR5","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abg3013","volume":"7","author":"L Fumagalli","year":"2021","unstructured":"Fumagalli, L. et al. C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility. Sci. Adv. 7, eabg3013 https:\/\/doi.org\/10.1126\/sciadv.abg3013 (2021).","journal-title":"Sci. Adv."},{"key":"2464_CR6","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1007\/s00401-020-02252-5","volume":"141","author":"AR Mehta","year":"2021","unstructured":"Mehta, A. R. et al. Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis. Acta Neuropathol. 141, 257\u2013279 https:\/\/doi.org\/10.1007\/s00401-020-02252-5 (2021).","journal-title":"Acta Neuropathol."},{"key":"2464_CR7","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.neures.2017.09.011","volume":"126","author":"K Yamanaka","year":"2018","unstructured":"Yamanaka, K. & Komine, O. The multi-dimensional roles of astrocytes in ALS. Neurosci. Res. 126, 31\u201338 https:\/\/doi.org\/10.1016\/j.neures.2017.09.011 (2018).","journal-title":"Neurosci. Res."},{"key":"2464_CR8","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00824","volume":"14","author":"M Izrael","year":"2020","unstructured":"Izrael, M., Slutsky, S. G. & Revel, M. Rising stars: astrocytes as a therapeutic target for ALS disease. Front. Neurosci. 14, 824 https:\/\/doi.org\/10.3389\/fnins.2020.00824 (2020).","journal-title":"Front. Neurosci."},{"key":"2464_CR9","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/S0896-6273(00)80997-6","volume":"20","author":"CLG Lin","year":"1998","unstructured":"Lin, C. L. G. et al. Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 20, 589\u2013602 https:\/\/doi.org\/10.1016\/S0896-6273(00)80997-6 (1998).","journal-title":"Neuron"},{"key":"2464_CR10","doi-asserted-by":"publisher","first-page":"3771","DOI":"10.1093\/brain\/awz302","volume":"142","author":"SP Allen","year":"2019","unstructured":"Allen, S. P. et al. C9orf72 expansion within astrocytes reduces metabolic flexibility in amyotrophic lateral sclerosis. Brain 142, 3771\u20133790 https:\/\/doi.org\/10.1093\/brain\/awz302 (2019).","journal-title":"Brain"},{"key":"2464_CR11","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1002\/glia.23761","volume":"68","author":"C Zhao","year":"2020","unstructured":"Zhao, C. et al. Mutant C9orf72 human iPSC-derived astrocytes cause non-cell autonomous motor neuron pathophysiology. Glia 68, 1046\u20131064 https:\/\/doi.org\/10.1002\/glia.23761 (2020).","journal-title":"Glia"},{"key":"2464_CR12","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/s41467-017-02729-0","volume":"9","author":"BT Selvaraj","year":"2018","unstructured":"Selvaraj, B. T. et al. C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity. Nat. Commun. 9, 347 https:\/\/doi.org\/10.1038\/s41467-017-02729-0 (2018).","journal-title":"Nat. Commun."},{"key":"2464_CR13","doi-asserted-by":"publisher","first-page":"e75500","DOI":"10.7554\/eLife.75500","volume":"11","author":"A-P Tosolini","year":"2022","unstructured":"Tosolini, A.-P. et al. BDNF-dependent modulation of axonal transport is selectively impaired in ALS. Elife 11, e75500 https:\/\/doi.org\/10.7554\/eLife.75500 (2022).","journal-title":"Elife"},{"key":"2464_CR14","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1016\/j.cmet.2011.08.016","volume":"14","author":"M B\u00e9langer","year":"2011","unstructured":"B\u00e9langer, M., Allaman, I. & Magistretti, P. J. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab. 14, 724\u2013738 https:\/\/doi.org\/10.1016\/j.cmet.2011.08.016 (2011).","journal-title":"Cell Metab."},{"key":"2464_CR15","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1111\/jnc.13486","volume":"139","author":"JP Bola\u00f1os","year":"2016","unstructured":"Bola\u00f1os, J. P. Bioenergetics and redox adaptations of astrocytes to neuronal activity. J. Neurochem. 139, 115\u2013125 https:\/\/doi.org\/10.1111\/jnc.13486 (2016).","journal-title":"J. Neurochem."},{"key":"2464_CR16","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1038\/s41418-017-0020-4","volume":"25","author":"NMC Connolly","year":"2018","unstructured":"Connolly, N. M. C. et al. Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases. Cell Death Differ. 25, 542\u2013572 https:\/\/doi.org\/10.1038\/s41418-017-0020-4 (2018).","journal-title":"Cell Death Differ."},{"key":"2464_CR17","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.mito.2019.08.001","volume":"49","author":"N Kozhukhar","year":"2019","unstructured":"Kozhukhar, N. & Alexeyev, M. F. Limited predictive value of TFAM in mitochondrial biogenesis. Mitochondrion 49, 156\u2013165 https:\/\/doi.org\/10.1016\/j.mito.2019.08.001 (2019).","journal-title":"Mitochondrion"},{"key":"2464_CR18","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1016\/j.cell.2012.12.029","volume":"152","author":"D Zala","year":"2013","unstructured":"Zala, D. et al. Vesicular glycolysis provides on-board energy for fast axonal transport. Cell 152, 479\u2013491 https:\/\/doi.org\/10.1016\/j.cell.2012.12.029 (2013).","journal-title":"Cell"},{"key":"2464_CR19","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/S0092-8674(00)80611-X","volume":"98","author":"Z Wu","year":"1999","unstructured":"Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115\u2013124 https:\/\/doi.org\/10.1016\/S0092-8674(00)80611-X (1999).","journal-title":"Cell"},{"key":"2464_CR20","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.cmet.2005.05.004","volume":"1","author":"J Lin","year":"2005","unstructured":"Lin, J., Handschin, C. & Spiegelman, B. M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361\u2013370 https:\/\/doi.org\/10.1016\/j.cmet.2005.05.004 (2005).","journal-title":"Cell Metab."},{"key":"2464_CR21","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1016\/j.cmet.2012.03.003","volume":"15","author":"S Da Cruz","year":"2012","unstructured":"Da Cruz, S. et al. Elevated PGC-1\u03b1 activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS. Cell Metab. 15, 778\u2013786 https:\/\/doi.org\/10.1016\/j.cmet.2012.03.003 (2012).","journal-title":"Cell Metab."},{"key":"2464_CR22","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1007\/978-1-0716-1990-2_16","volume":"2431","author":"AR Mehta","year":"2022","unstructured":"Mehta, A. R., Chandran, S. & Selvaraj, B. T. Assessment of mitochondrial trafficking as a surrogate for fast axonal transport in human induced pluripotent stem cell-derived spinal motor neurons. Methods Mol. Biol. 2431, 311\u2013322 (2022).","journal-title":"Methods Mol. Biol."},{"key":"2464_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15132","volume":"8","author":"P Hasel","year":"2017","unstructured":"Hasel, P. et al. Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism. Nat. Commun. 8, 15132 https:\/\/doi.org\/10.1038\/ncomms15132 (2017).","journal-title":"Nat. Commun."},{"key":"2464_CR24","unstructured":"R Core Team R: A Language and Environment for Statistical Computing (R Core Team 2023)."},{"key":"2464_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v067.i01","volume":"67","author":"D Bates","year":"2015","unstructured":"Bates, D., Maechler, M., Bolker, B. & Walker, S. Fitting linear mixed-effects models using lme4. J. Stat. Softw. 67, 1\u201348 https:\/\/doi.org\/10.18637\/jss.v067.i01 (2015).","journal-title":"J. Stat. Softw."},{"key":"2464_CR26","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-11-5","volume":"11","author":"SE Lazic","year":"2010","unstructured":"Lazic, S. E. The problem of pseudoreplication in neuroscientific studies: is it affecting your analysis? BMC Neurosci. 11, 5 https:\/\/doi.org\/10.1186\/1471-2202-11-5 (2010).","journal-title":"BMC Neurosci."},{"key":"2464_CR27","unstructured":"Fox, J. & Weisberg, S. An R Companion to Applied Regression 3rd edn (Sage, 2019)."},{"key":"2464_CR28","unstructured":"Lenth, R. & Piaskowski, J. emmeans: Estimated marginal means, aka least-squares means. GitHub https:\/\/rvlenth.github.io\/emmeans\/ (2026)."},{"key":"2464_CR29","doi-asserted-by":"publisher","first-page":"11929","DOI":"10.1523\/JNEUROSCI.1860-14.2014","volume":"34","author":"Y Zhang","year":"2014","unstructured":"Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929\u201311947 https:\/\/doi.org\/10.1523\/JNEUROSCI.1860-14.2014 (2014).","journal-title":"J. Neurosci."},{"key":"2464_CR30","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 https:\/\/doi.org\/10.1186\/s13059-014-0550-8 (2014).","journal-title":"Genome Biol."}],"container-title":["Nature Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41593-026-02464-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41593-026-02464-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41593-026-02464-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T09:02:43Z","timestamp":1791363763000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41593-026-02464-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":30,"alternative-id":["2464"],"URL":"https:\/\/doi.org\/10.1038\/s41593-026-02464-0","relation":{},"ISSN":["1097-6256","1546-1726"],"issn-type":[{"value":"1097-6256","type":"print"},{"value":"1546-1726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]},"assertion":[{"value":"13 February 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 October 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}