{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T03:20:36Z","timestamp":1791084036855,"version":"4.1.0"},"reference-count":102,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorder","doi-asserted-by":"crossref","award":["RO1NS107417"],"award-info":[{"award-number":["RO1NS107417"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorder","doi-asserted-by":"crossref","award":["RO1NS102479"],"award-info":[{"award-number":["RO1NS102479"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Joseph Beckman ALS Research Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Mutations in the gene encoding the p150 subunit of the dynactin complex (DCTN1) are linked to amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Perry syndrome. These neurodegenerative diseases can cause muscle weakness and atrophy, parkinsonian-like symptoms, and paralysis. To examine the evolution of neuropathology caused by a mutation in DCTN1 and cellular mechanisms of disease for therapeutic discovery, we characterized mice expressing either human wildtype or mutant (G59S) DCTN1. Neuron-specific expression of mutant, but not wildtype, DCTN1 caused fatal age-related paralytic disease and motor neuron (MN) degeneration in the spinal cord with axonopathy and chromatolysis without apoptotic morphology. MNs became positive for cleaved caspase-3, cleaved caspase-8, and nitrated Hsp90. Mitochondria accumulated and appeared fragmented and dysmorphic and then were lost. This pathology was accompanied by invasion of CD95- and CD8-positive mononuclear T cells into the ventral horn and accumulation of TNF\u03b1 and IL9. Administration of the mitochondrial division inhibitor-1 (Mdivi-1) protected MNs and extended the lifespan of G59S-DCTN1 mice. A mitochondrial permeability transition pore inhibitor also extended lifespan. Thus, mutant DCTN1 causes degeneration of MNs associated with axonopathy, mitochondriopathy, nitrative stress, and caspase activation. It appears as retrograde neurodegeneration and inflammatory T-cell-like cytolysis. Mitochondria are possible therapeutic targets in DCTN1-linked neurodegenerative disorders.<\/jats:p>","DOI":"10.3390\/biom15121637","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T12:41:58Z","timestamp":1763728918000},"page":"1637","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Human Mutant Dynactin Subunit 1 Causes Profound Motor Neuron Disease Consistent with Possible Mechanisms Involving Axonopathy, Mitochondriopathy, Protein Nitration, and T-Cell-Mediated Cytolysis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7562-303X","authenticated-orcid":false,"given":"Victor","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Pathology, Neuropathology Division, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7971-9805","authenticated-orcid":false,"given":"Maria Clara","family":"Franco","sequence":"additional","affiliation":[{"name":"Center for Translation Science, Herbert Wertheim College of Medicine, Florida International University, Port St. Lucie, FL 33199, USA"},{"name":"Department of Cellular & Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Port St. Lucie, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8961-7020","authenticated-orcid":false,"given":"Lee J.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Neuropathology Division, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Pathobiology Graduate Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/ng1123","article-title":"Mutant dynactin in motor neuron disease","volume":"33","author":"Puls","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1002\/ana.20468","article-title":"Distal spinal and bulbar muscular atrophy caused by dynactin mutation","volume":"57","author":"Puls","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1212\/01.WNL.0000134608.83927.B1","article-title":"Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS","volume":"63","author":"Sedlmeier","year":"2004","journal-title":"Neurology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.14802\/jmd.20060","article-title":"Perry Disease: Concept of a New Disease and Clinical Diagnostic Criteria","volume":"14","author":"Tsuboi","year":"2021","journal-title":"J. Mov. Disord."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1083\/jcb.115.6.1639","article-title":"Dynactin, a conserved, ubiquitously expressed component of an activator of vesicle motility mediated by cytoplasmic dynein","volume":"115","author":"Gill","year":"1991","journal-title":"J. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1146\/annurev.ph.53.030191.003213","article-title":"Functions of microtubule-based motors","volume":"53","author":"Schroer","year":"1991","journal-title":"Annu. Rev. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1146\/annurev.cellbio.20.012103.094623","article-title":"Dynactin","volume":"20","author":"Schroer","year":"2004","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nrn1624","article-title":"Molecular Motors and mechanisms of directional transport in neurons","volume":"6","author":"Hirokawa","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/S0896-6273(02)00696-7","article-title":"Disruption of dynein\/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration","volume":"34","author":"LaMonte","year":"2002","journal-title":"Neuron"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/ncb1421","article-title":"Processive bidirectional motion of dynein\u2013dynactin complexes in vitro","volume":"8","author":"Ross","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/ng1591","article-title":"Dynein mutations impair autophagic clearance of aggregate-prone proteins","volume":"37","author":"Ravikumar","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5147","DOI":"10.1073\/pnas.0810828106","article-title":"Neurodegeneration mutations in dynactin impair dynein-dependent nuclear migration","volume":"106","author":"Moore","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.devcel.2018.07.001","article-title":"Retrograde degenerative signaling mediated by the P75 neurotrophin receptor requires p150glued deacetylation by axonal HDAC1","volume":"46","author":"Pathak","year":"2018","journal-title":"Dev. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5350","DOI":"10.1096\/fj.201700759RR","article-title":"Nitration of microtubules blocks axonal mitochondrial transport in a human pluripotent stem cell model of Parkinson\u2019s disease","volume":"32","author":"Stykel","year":"2018","journal-title":"FASEB J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1083\/jcb.200511068","article-title":"A motor neuron disease-associated mutation in p150Glued perturbs dynactin function and induces protein aggregation","volume":"172","author":"Levy","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.neuron.2012.02.025","article-title":"Dynactin is required for transport initiation from the distal axon","volume":"74","author":"Moughamian","year":"2012","journal-title":"Neuron"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.neuron.2012.02.026","article-title":"The p150Glued CAP-Gly domain regulates initiation of retrograde transport at synaptic termini","volume":"74","author":"Lloyd","year":"2012","journal-title":"Neuron"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1091\/mbc.e05-06-0526","article-title":"Kinesin-1 and Dynein are the primary motors for fast transport of mitochondria in Drosophila motor axons","volume":"17","author":"Pilling","year":"2006","journal-title":"Mol. Biol. Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0074-7742(08)60183-X","article-title":"The axon reaction: A review of the principal features of perikaryal responses to axon injury","volume":"14","author":"Lieberman","year":"1971","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1083\/jcb.53.1.24","article-title":"The response of ventral horn neurons to axonal transection","volume":"53","author":"Price","year":"1972","journal-title":"J. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0361-9230(98)00024-0","article-title":"Neurodegeneration in excitotoxicity, lobal cerebral ischemia, and target deprivation: A perspective on the contributions of apoptosis and necrosis","volume":"46","author":"Martin","year":"1998","journal-title":"Brain Res. Bull."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0165-0270(96)00121-5","article-title":"Overexpression of growth-associated proteins in the neurons of adult transgenic mice","volume":"71","author":"Caroni","year":"1997","journal-title":"J. Neurosc. Meth."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1523\/JNEUROSCI.4231-07.2008","article-title":"Motor neuron disease occurring in a mutant dynactin mouse model is characterized by defects in vesicular trafficking","volume":"28","author":"Laird","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/1750-1326-6-75","article-title":"Generation and characterization of transgenic mice expressing mitochondrial targeted red fluorescent protein selectively in neurons: Modeling mitochondriopathy in excitotoxicity and amyotrophic lateral sclerosis","volume":"6","author":"Wang","year":"2011","journal-title":"Mol. Neurodegener."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0896-6273(00)00084-2","article-title":"Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP","volume":"28","author":"Feng","year":"2000","journal-title":"Neuron"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1083\/jcb.135.4.883","article-title":"In situ localization of mitochondrial DNA replication in intact mammalian cells","volume":"135","author":"Davis","year":"1996","journal-title":"J. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1002\/cne.21012","article-title":"The adult neural stem and progenitor cell niche is altered in amyotrophic lateral sclerosis mouse brain","volume":"497","author":"Liu","year":"2006","journal-title":"J. Comp. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1523\/JNEUROSCI.2225-10.2011","article-title":"The mitochondrial permeability transition pore regulates nitric oxide-mediated apoptosis of neurons induced by target deprivation","volume":"31","author":"Martin","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Martin, L.J., Fancelli, D., Wong, M., Niedzwiecki, M., Ballarini, M., Plyte, S., and Chang, Q. (2014). GNX-4728, a novel small molecule drug inhibitor of mitochondrial permeability transition, is therapeutic in a mouse model of amyotrophic lateral sclerosis. Front. Cell. Neurosci., 8.","DOI":"10.3389\/fncel.2014.00433"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1097\/nen.0b013e318158822b","article-title":"Adult olfactory bulb neural precursor cell grafts provide temporary protection from motor neuron degeneration, improve motor function, and extend survival in amyotrophic lateral sclerosis mice","volume":"66","author":"Martin","year":"2007","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1093\/hmg\/ddq106","article-title":"Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice","volume":"19","author":"Wong","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","first-page":"1358","article-title":"Synaptic pathology and glial responses to neuronal injury precede the formation of senile plaques and amyloid deposits in the aging cerebral cortex","volume":"145","author":"Martin","year":"1994","journal-title":"Am. J. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/(SICI)1096-9861(19970203)378:1<88::AID-CNE5>3.0.CO;2-G","article-title":"Non-NMDA and NMDA receptor-mediated excitotoxic neuronal deaths in adult brain are morphologically distinct: Further evidence for an apoptosis-necrosis continuum","volume":"378","author":"Price","year":"1997","journal-title":"J. Comp. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/cne.21160","article-title":"Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: Mechanisms of mitochondriopathy and cell death","volume":"500","author":"Martin","year":"2007","journal-title":"J. Comp. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1177\/25.9.333018","article-title":"The unlabeled antibody enzyme method. Attempted use of peroxidase-conjugated antigen as the third layer in the technique","volume":"25","author":"Sternberger","year":"1977","journal-title":"J. Histochem. Cytochem."},{"key":"ref_36","first-page":"165","article-title":"The peroxidase-antiperoxidase (PAP) method","volume":"34","author":"Bratthauer","year":"1994","journal-title":"Methods Mol. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"E1102","DOI":"10.1073\/pnas.1215177110","article-title":"Nitration of Hsp90 induces cell death","volume":"110","author":"Franco","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/351579a0","article-title":"Homology of a 150K cytoplasmic dynein-associated polypeptide with the drosophila gene glued","volume":"351","author":"Holzbaur","year":"1991","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6449","DOI":"10.1523\/JNEUROSCI.0911-05.2005","article-title":"Adult motor neuron apoptosis is mediated by nitric oxide and Fas death receptor linked by DNA damage and p53 activation","volume":"25","author":"Martin","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/j.1365-2990.1976.tb00516.x","article-title":"Central chromatolysis and the axon reaction: A reappraisal","volume":"2","author":"Torvik","year":"1976","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1002\/(SICI)1097-4695(199908)40:2<185::AID-NEU5>3.0.CO;2-#","article-title":"Motor neuron degeneration after sciatic nerve avulsion in adult rat evolves with oxidative stress and is apoptosis","volume":"40","author":"Martin","year":"1999","journal-title":"J. Neurobiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4793","DOI":"10.1016\/S0021-9258(19)43735-6","article-title":"Mitochondrial superoxide dismutase site of synthesis and intramitochondrial localization","volume":"248","author":"Weisiger","year":"1973","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"706","DOI":"10.4161\/auto.5.5.8505","article-title":"Parkin-induced mitophagy in the pathogenesis of Parkinson disease","volume":"5","author":"Narendra","year":"2009","journal-title":"Autophagy"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.bbadis.2009.07.009","article-title":"The mitochondrial permeability transition pore: A molecular target for amyotrophic lateral sclerosis therapy","volume":"1802","author":"Martin","year":"2010","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1097\/01.jnen.0000248541.05552.c4","article-title":"Mitochondriopathy in Parkinson disease and amyotrophic lateral sclerosis","volume":"65","author":"Martin","year":"2006","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/neu.10026","article-title":"Injury-induced spinal motor neuron apoptosis is preceded by DNA single-strand breaks and is p53- and Bax-dependent","volume":"50","author":"Martin","year":"2002","journal-title":"J. Neurobiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"839","DOI":"10.3390\/ph3040839","article-title":"Mitochondrial and cell death mechanisms in neurodegenerative diseases","volume":"3","author":"Martin","year":"2010","journal-title":"Pharmaceuticals"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Parrish, A.B., Freel, C.D., and Kornbluth, S. (2013). Cellular mechanisms controlling caspase activation and function. Cold Spring Harb. Perspect. Biol., 5.","DOI":"10.1101\/cshperspect.a008672"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/364584a0","article-title":"ALS, SOD and peroxynitrite","volume":"364","author":"Beckman","year":"1993","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1126\/science.286.5449.2498","article-title":"Induction of nitric oxide\u2014Dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase","volume":"286","author":"Crow","year":"1999","journal-title":"Science"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s00429-009-0226-4","article-title":"Inducible nitric oxide synthase is present in motor neuron mitochondria and schwann cells and contributes to disease mechanisms in ALS mice","volume":"214","author":"Chen","year":"2010","journal-title":"Brain Struct. Funct."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.1016\/j.neurobiolaging.2014.07.003","article-title":"Identify mutation in amyotrophic lateral sclerosis cases using HaloPlex target enrichment system","volume":"35","author":"Liu","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_53","unstructured":"Dulski, J., Konno, T., and Wszolek, Z. (2010). DCTN1-related neurodegeneration. GeneReviews\u00ae, University of Washington."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/ng.293","article-title":"DCTN1 mutations in Perry syndrome","volume":"41","author":"Farrer","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.parkreldis.2017.06.004","article-title":"DCTN1-related neurodegeneration: Perry syndrome and beyond","volume":"41","author":"Konno","year":"2017","journal-title":"Park. Relat. Disord."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1212\/WNL.0b013e3181a92c4c","article-title":"Characterization of DCTN1 genetic variability in neurodegeneration","volume":"72","author":"Wider","year":"2009","journal-title":"Neurology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e22234","DOI":"10.7554\/eLife.22234","article-title":"Regulation of mitochondria-dynactin interaction and mitochondrial retrograde transport in axons","volume":"6","author":"Drerup","year":"2017","journal-title":"eLife"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"14819","DOI":"10.1038\/ncomms14819","article-title":"Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration","volume":"8","author":"Kononenko","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4807","DOI":"10.1038\/ncomms5807","article-title":"Dynactin functions as both a dynamic tether and brake during dynein-driven motility","volume":"5","author":"Ayloo","year":"2014","journal-title":"Nat. Comm."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"13982","DOI":"10.1523\/JNEUROSCI.4226-07.2007","article-title":"The G59S mutation in p150glued causes dysfunction of dynactin in mice","volume":"27","author":"Lai","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1093\/hmg\/ddn092","article-title":"Lysosomal proliferation and distal degeneration in motor neurons expressing the G59S mutation in the p150Glued subunit of dynactin","volume":"17","author":"Wallace","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1523\/JNEUROSCI.18-09-03241.1998","article-title":"Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1","volume":"18","author":"Kong","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1006\/nbdi.2000.0299","article-title":"Human Cu\/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial vacuolization, axonal degeneration, and premature motoneuron death and accelerates motoneuron disease in mice expressing a familial amyotrophic lateral sclerosis mutant SOD1","volume":"7","author":"Jaarsma","year":"2000","journal-title":"Neurobiol. Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.expneurol.2009.02.015","article-title":"The mitochondrial permeability transition pore in motor neurons: Involvement in the pathobiology of ALS mice","volume":"218","author":"Martin","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.tins.2010.03.006","article-title":"Retrograde axonal transport: Pathways to cell death?","volume":"33","author":"Perlson","year":"2010","journal-title":"Trends Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4578","DOI":"10.1038\/s41467-021-24862-7","article-title":"Mitochondrial adaptor TRAK2 activates and functionally links opposing kinesin and dynein motors","volume":"12","author":"Fenton","year":"2021","journal-title":"Nat. Comm."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.nbd.2011.01.016","article-title":"Calcium dysregulation, mitochondrial pathology and protein aggregation in a culture model of amyotrophic lateral sclerosis: Mechanistic relationship and differential sensitivity to intervention","volume":"42","author":"Tradewell","year":"2011","journal-title":"Neurobiol. Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2132","DOI":"10.1056\/NEJMcibr1003521","article-title":"The mitochondrion\u2014A trojan horse that kicks off inflammation?","volume":"362","author":"Manfredi","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s12974-025-03363-0","article-title":"Mitochondrial DNA leakage: Underlying mechanisms and therapeutic implications in neurological disorders","volume":"22","author":"Zhang","year":"2025","journal-title":"J. Neuroinflammation"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"96","DOI":"10.14336\/AD.2023.0519","article-title":"The inflammatory puzzle: Piecing together the links between neuroinflammation and amyotrophic lateral sclerosis","volume":"15","author":"He","year":"2024","journal-title":"Aging Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s13024-023-00672-x","article-title":"Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders","volume":"18","author":"Huang","year":"2023","journal-title":"Mol. Neurodegener."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Cunha-Oliveira, T., Montezinho, L., Sim\u00f5es, R.F., Carvalho, M., Ferreiro, E., and Silva, F.S.G. (2024). Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis. Cells, 13.","DOI":"10.3390\/cells13030248"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1182\/blood.V90.5.1952","article-title":"Fas-Fas ligand-based interactions between tumor cells and tumor-specific cytotoxic T lymphocytes: A lethal two-way street","volume":"90","author":"Zeytun","year":"1997","journal-title":"Blood"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.4049\/jimmunol.1700420","article-title":"Many Th Cell Subsets Have Fas Ligand-Dependent Cytotoxic Potential","volume":"200","author":"Kotov","year":"2018","journal-title":"J. Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Duan, Z., and Cui, Y. (2023). CD8+ T cells in brain injury and neurodegeneration. Front. Cell. Neurosci., 17.","DOI":"10.3389\/fncel.2023.1281763"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"11397","DOI":"10.1523\/JNEUROSCI.0602-06.2006","article-title":"Absence of tumor necrosis factor-alpha does not affect motor neuron disease caused by superoxide dismutase 1 mutations","volume":"26","author":"Gowing","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/978-1-4939-6877-0_2","article-title":"IL-9: Function, Sources, and Detection","volume":"Volume 1585","author":"Clifton","year":"2017","journal-title":"Methods in Molecular Biology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/nm.2856","article-title":"Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells","volume":"18","author":"Purwar","year":"2012","journal-title":"Nat. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.yexmp.2015.07.010","article-title":"IL-9 signaling affects central nervous system resident cells during inflammatory stimuli","volume":"99","author":"Ding","year":"2015","journal-title":"Exp. Mol. Pathol."},{"key":"ref_80","first-page":"691","article-title":"Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue","volume":"140","author":"Kawamata","year":"1992","journal-title":"Am. J. Pathol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nm0202-185","article-title":"Visualization and quantification of T cell-mediated cytotoxicity using cell-permeable fluorogenic caspase substrates","volume":"8","author":"Liu","year":"2002","journal-title":"Nat. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/NEN.0b013e31816ff780","article-title":"DNA damage and repair: Relevance to mechanisms of neurodegeneration","volume":"67","author":"Martin","year":"2008","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/S1097-2765(02)00442-2","article-title":"Three-dimensional structure of the apoptosome: Implications for assembly, procaspase-9 binding, and activation","volume":"9","author":"Acehan","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e17755","DOI":"10.7554\/eLife.17755","article-title":"A near atomic structure of the active human apoptosome","volume":"5","author":"Cheng","year":"2016","journal-title":"eLife"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Ishikawa, K.-I., Saiki, S., Furuya, N., Yamada, D., Imamichi, Y., Li, Y., Kawajiri, S., Sasaki, H., Koike, M., and Tsuboi, Y. (2014). P150glued-associated disorders are caused by activation of intrinsic apoptotic pathway. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0094645"},{"key":"ref_86","first-page":"505","article-title":"Mdivi-1: A promising drug and its underlying mechanisms in the treatment of neurodegenerative diseases","volume":"37","author":"Liu","year":"2022","journal-title":"Histol. Histopathol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1091\/mbc.12.8.2245","article-title":"Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells","volume":"12","author":"Smirnova","year":"2001","journal-title":"MBoC"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e8166","DOI":"10.15252\/emmm.201708166","article-title":"Inhibition of Drp1\/Fis1 interaction slows progression of amyotrophic lateral sclerosis","volume":"10","author":"Joshi","year":"2018","journal-title":"EMBO Mol. Med."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Ciuro, M., Sangiorgio, M., Cacciato, V., Cantone, G., Fichera, C., Salvatorelli, L., Magro, G., Leanza, G., Vecchio, M., and Valle, M.S. (2024). Mitigating the functional deficit after neurotoxic motoneuronal loss by an inhibitor of mitochondrial fission. IJMS, 25.","DOI":"10.3390\/ijms25137059"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Bido, S., Soria, F.N., Fan, R.Z., Bezard, E., and Tieu, K. (2017). Mitochondrial division inhibitor-1 is neuroprotective in the A53T-\u03b1-synuclein rat model of Parkinson\u2019s disease. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-07181-0"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1046\/j.1471-4159.2004.02363.x","article-title":"Induction of motor neuron apoptosis by free 3-nitro-L-tyrosine","volume":"89","author":"Peluffo","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/cne.1087","article-title":"Motor neurons rapidly accumulate DNA single-strand breaks after in vitro exposure to nitric oxide and peroxynitrite and in vivo axotomy","volume":"432","author":"Liu","year":"2001","journal-title":"J. Comp. Neurol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/0304-3940(95)12039-7","article-title":"Induction of nitrotyrosine-like immunoreactivity in the lower motor neuron of amyotrophic lateral sclerosis","volume":"199","author":"Abe","year":"1995","journal-title":"Neurosci. Lett."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/0891-0618(96)00137-8","article-title":"Colocalization of NOS and SOD1 in neurofilament accumulation within motor neurons of amyotrophic lateral sclerosis: An immunohistochemical Study","volume":"10","author":"Chou","year":"1996","journal-title":"J. Chem. Neuroanat."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1002\/ana.410420416","article-title":"Incrased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis","volume":"42","author":"Beal","year":"1997","journal-title":"Ann. Neurol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/S0006-8993(99)02302-1","article-title":"Immunocytochemical study on the distribution of nitrotyrosine in the brain of the transgenic mice expressing a human Cu\/Zn SOD mutation","volume":"853","author":"Cha","year":"2000","journal-title":"Brain Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/jcp.1030210305","article-title":"Some chemical mechanisms in chromatolysis","volume":"21","author":"Gersh","year":"1943","journal-title":"J. Cell. Comp. Physiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0006-8993(70)90345-8","article-title":"What is the signal for chromatolysis?","volume":"23","author":"Cragg","year":"1970","journal-title":"Brain Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/BF00687142","article-title":"Ultrastructural study of chromatolytic neurons in an adult-onset sporadic case of amyotrophic lateral sclerosis","volume":"75","author":"Kusaka","year":"1988","journal-title":"Acta Neuropathol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1097\/00005072-199905000-00005","article-title":"Neuronal death in amyotrophic lateral sclerosis is apoptosis: Possible contribution of a programmed cell death mechanism","volume":"58","author":"Martin","year":"1999","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Logan, I.E., Nguyen, K.T., Chatterjee, T., Manivannan, B., Paul, N.P., Kim, S.R., Sixta, E.M., Bastian, L.P., Marean-Reardon, C., and Karajannis, M.A. (2024). Selective nitration of Hsp90 acts as a metabolic switch promoting tumor cell proliferation. Redox Biol., 75.","DOI":"10.1016\/j.redox.2024.103249"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.semcancer.2017.02.003","article-title":"Cellular acidification as a new approach to cancer treatment and to the understanding and therapeutics of neurodegenerative diseases","volume":"43","author":"Harguindey","year":"2017","journal-title":"Semin. Cancer Biol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/12\/1637\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,23]],"date-time":"2025-11-23T05:28:07Z","timestamp":1763875687000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/12\/1637"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,21]]},"references-count":102,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["biom15121637"],"URL":"https:\/\/doi.org\/10.3390\/biom15121637","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,21]]}}}