{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:43:52Z","timestamp":1786409032914,"version":"build-2736575974"},"reference-count":87,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T00:00:00Z","timestamp":1640736000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003621","name":"Ministry of Science ICT and Future Planning","doi-asserted-by":"publisher","award":["2019R1F1A1045639, 2020R1A2C4002366"],"award-info":[{"award-number":["2019R1F1A1045639, 2020R1A2C4002366"]}],"id":[{"id":"10.13039\/501100003621","id-type":"DOI","asserted-by":"publisher"}]},{"name":"KBRI Research Program of the Ministry of Science, ICT and Future Planning","award":["21-BR-02-15"],"award-info":[{"award-number":["21-BR-02-15"]}]},{"name":"the Soonchunhyang University Research Fund","award":["Kiyoung Kim"],"award-info":[{"award-number":["Kiyoung Kim"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>TAR DNA-binding protein 43 (TDP-43) is a member of an evolutionarily conserved family of heterogeneous nuclear ribonucleoproteins that modulate multiple steps in RNA metabolic processes. Cytoplasmic aggregation of TDP-43 in affected neurons is a pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer\u2019s disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Mislocalized and accumulated TDP-43 in the cytoplasm induces mitochondrial dysfunction and reactive oxidative species (ROS) production. Here, we show that TDP-43- and rotenone-induced neurotoxicity in the human neuronal cell line SH-SY5Y were attenuated by hydroxocobalamin (Hb, vitamin B12 analog) treatment. Although Hb did not affect the cytoplasmic accumulation of TDP-43, Hb attenuated TDP-43-induced toxicity by reducing oxidative stress and mitochondrial dysfunction. Moreover, a shortened lifespan and motility defects in TDP-43-expressing Drosophila were significantly mitigated by dietary treatment with hydroxocobalamin. Taken together, these findings suggest that oral intake of hydroxocobalamin may be a potential therapeutic intervention for TDP-43-associated proteinopathies.<\/jats:p>","DOI":"10.3390\/antiox11010082","type":"journal-article","created":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T08:12:15Z","timestamp":1640765535000},"page":"82","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Vitamin B12 Reduces TDP-43 Toxicity by Alleviating Oxidative Stress and Mitochondrial Dysfunction"],"prefix":"10.3390","volume":"11","author":[{"given":"Yu-Mi","family":"Jeon","sequence":"first","affiliation":[{"name":"Dementia Research Group, Korea Brain Research Institute, Daegu 41068, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Younghwi","family":"Kwon","sequence":"additional","affiliation":[{"name":"Dementia Research Group, Korea Brain Research Institute, Daegu 41068, Korea"},{"name":"Department of Brain and Cognitive Sciences, DGIST, Daegu 41068, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinrye","family":"Lee","sequence":"additional","affiliation":[{"name":"Dementia Research Group, Korea Brain Research Institute, Daegu 41068, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Dementia Research Group, Korea Brain Research Institute, Daegu 41068, Korea"},{"name":"Department of Brain and Cognitive Sciences, DGIST, Daegu 41068, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myungjin","family":"Jo","sequence":"additional","affiliation":[{"name":"Dementia Research Group, Korea Brain Research Institute, Daegu 41068, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8012-9749","authenticated-orcid":false,"given":"Seongsoo","family":"Lee","sequence":"additional","affiliation":[{"name":"Gwangju Center, Korea Basic Science Institute, Gwangju 61886, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0299-1613","authenticated-orcid":false,"given":"Sang Ryong","family":"Kim","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Kyungpook National University, Daegu 41566, Korea"},{"name":"BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4879-5207","authenticated-orcid":false,"given":"Kiyoung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology, Soonchunhyang University, Asan 31538, Korea"},{"name":"Department of Medical Sciences, Soonchunhyang University, Asan 31538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3385-5510","authenticated-orcid":false,"given":"Hyung-Jun","family":"Kim","sequence":"additional","affiliation":[{"name":"Dementia Research Group, Korea Brain Research Institute, Daegu 41068, Korea"},{"name":"Department of Brain and Cognitive Sciences, DGIST, Daegu 41068, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3584","DOI":"10.1128\/jvi.69.6.3584-3596.1995","article-title":"Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs","volume":"69","author":"Ou","year":"1995","journal-title":"J. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jmb.2011.11.003","article-title":"UG repeats\/TDP-43 interactions near 5\u2032 splice sites exert unpredictable effects on splicing modulation","volume":"415","author":"Passoni","year":"2012","journal-title":"J. Mol. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5062","DOI":"10.1093\/nar\/gkt189","article-title":"Characterizing TDP-43 interaction with its RNA targets","volume":"41","author":"Bhardwaj","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"13302","DOI":"10.1074\/jbc.M800342200","article-title":"Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation","volume":"283","author":"Winton","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s00401-018-1875-2","article-title":"Nucleo-cytoplasmic transport of TDP-43 studied in real time: Impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons","volume":"136","author":"Svahn","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1097\/NEN.0b013e31822c62cf","article-title":"Accumulation of transactive response DNA binding protein 43 in mild cognitive impairment and Alzheimer disease","volume":"70","author":"Tremblay","year":"2011","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s00401-007-0226-5","article-title":"TDP-43 proteinopathy: The neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease","volume":"114","author":"Kwong","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00401-011-0845-8","article-title":"A harmonized classification system for FTLD-TDP pathology","volume":"122","author":"Mackenzie","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1093\/brain\/awz099","article-title":"Limbic-predominant age-related TDP-43 encephalopathy (LATE): Consensus working group report","volume":"142","author":"Nelson","year":"2019","journal-title":"Brain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/ng.132","article-title":"TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis","volume":"40","author":"Kabashi","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/S1474-4422(08)70071-1","article-title":"TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: A genetic and histopathological analysis","volume":"7","author":"Leverenz","year":"2008","journal-title":"Lancet Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1007\/s13311-015-0338-x","article-title":"TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets","volume":"12","author":"Scotter","year":"2015","journal-title":"Neurotherapeutics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/jnc.14327","article-title":"Pathomechanisms of TDP-43 in neurodegeneration","volume":"146","author":"Gao","year":"2018","journal-title":"J. Neurochem."},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1084\/jem.20111313","article-title":"Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor kappaB-mediated pathogenic pathways","volume":"208","author":"Swarup","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.expneurol.2015.07.019","article-title":"TDP-43 activates microglia through NF-kappaB and NLRP3 inflammasome","volume":"273","author":"Zhao","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1038\/nm.4130","article-title":"The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity","volume":"22","author":"Wang","year":"2016","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wang, P., Deng, J., Dong, J., Liu, J., Bigio, E.H., Mesulam, M., Wang, T., Sun, L., Wang, L., and Lee, A.Y. (2019). TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1007947"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.cell.2020.09.020","article-title":"TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS\/STING in ALS","volume":"183","author":"Yu","year":"2020","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"103396","DOI":"10.1016\/j.mcn.2019.103396","article-title":"TDP-43 proteinopathy and mitochondrial abnormalities in neurodegeneration","volume":"100","author":"Gao","year":"2019","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s40035-020-00219-w","article-title":"Maintaining the balance of TDP-43, mitochondria, and autophagy: A promising therapeutic strategy for neurodegenerative diseases","volume":"9","author":"Huang","year":"2020","journal-title":"Transl. Neurodegener."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.neulet.2018.04.053","article-title":"TDP-43 interacts with mitochondrial proteins critical for mitophagy and mitochondrial dynamics","volume":"678","author":"Davis","year":"2018","journal-title":"Neurosci. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"653688","DOI":"10.3389\/fncel.2021.653688","article-title":"The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS","volume":"15","author":"Dafinca","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.freeradbiomed.2009.11.018","article-title":"Oxidative stress in ALS: Key role in motor neuron injury and therapeutic target","volume":"48","author":"Barber","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1136\/jnnp-2018-319294","article-title":"Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: A long-term phase II\/III randomised controlled study","volume":"90","author":"Kaji","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"17040","DOI":"10.1038\/nrdp.2017.40","article-title":"Vitamin B12 deficiency","volume":"3","author":"Green","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jns.2005.03.009","article-title":"Vitamin B12, demyelination, remyelination and repair in multiple sclerosis","volume":"233","author":"Miller","year":"2005","journal-title":"J. Neurol. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/0304-3940(94)90272-0","article-title":"Methylcobalamin (methyl-B12) promotes regeneration of motor nerve terminals degenerating in anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mouse","volume":"170","author":"Yamazaki","year":"1994","journal-title":"Neurosci. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9968228","DOI":"10.1155\/2021\/9968228","article-title":"The Role of Neurotropic B Vitamins in Nerve Regeneration","volume":"2021","author":"Baltrusch","year":"2021","journal-title":"Biomed Res. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.molmed.2021.07.002","article-title":"Clinical implications of vitamin B12 as redox-active cofactor","volume":"27","author":"Offringa","year":"2021","journal-title":"Trends Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.freeradbiomed.2011.05.034","article-title":"Vitamin B12 protects against superoxide-induced cell injury in human aortic endothelial cells","volume":"51","author":"Moreira","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1046\/j.1365-2249.1999.00870.x","article-title":"Immunomodulation by vitamin B12: Augmentation of CD8+ T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by methyl-B12 treatment","volume":"116","author":"Tamura","year":"1999","journal-title":"Clin. Exp. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.brainresrev.2008.05.001","article-title":"Experimental and clinical evidence of the role of cytokines and growth factors in the pathogenesis of acquired cobalamin-deficient leukoneuropathy","volume":"59","author":"Scalabrino","year":"2008","journal-title":"Brain Res. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"481","DOI":"10.3233\/JAD-2010-1252","article-title":"Vitamin B12 levels in Alzheimer\u2019s disease: Association with clinical features and cytokine production","volume":"19","author":"Politis","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40734-020-00085-8","article-title":"Vitamin B12 measurements across neurodegenerative disorders","volume":"7","author":"Luthra","year":"2020","journal-title":"J. Clin. Mov. Disord."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ejcn.2014.165","article-title":"Treatment of vitamin B12 deficiency-methylcobalamine? Cyancobalamine? Hydroxocobalamin?-clearing the confusion","volume":"69","author":"Thakkar","year":"2015","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"801","DOI":"10.3945\/an.112.002535","article-title":"The role of B vitamins in preventing and treating cognitive impairment and decline","volume":"3","author":"Morris","year":"2012","journal-title":"Adv. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/ajh.2830340208","article-title":"Function of vitamin B12 in the central nervous system as revealed by congenital defects","volume":"34","author":"Hall","year":"1990","journal-title":"Am. J. Hematol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1002\/mnfr.201500019","article-title":"Cobalamin coenzyme forms are not likely to be superior to cyano- and hydroxyl-cobalamin in prevention or treatment of cobalamin deficiency","volume":"59","author":"Obeid","year":"2015","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"107492","DOI":"10.1016\/j.celrep.2020.03.056","article-title":"TBK1 and IKKepsilon Act Redundantly to Mediate STING-Induced NF-kappaB Responses in Myeloid Cells","volume":"31","author":"Balka","year":"2020","journal-title":"Cell Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3389\/fphar.2018.00520","article-title":"Bax\/Tubulin\/Epithelial-Mesenchymal Pathways Determine the Efficacy of Silybin Analog HM015k in Colorectal Cancer Cell Growth and Metastasis","volume":"9","author":"Amawi","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"122","DOI":"10.3892\/etm.2020.9250","article-title":"GSK-3beta mediates the effects of HNF-1beta overexpression in ovarian clear cell carcinoma","volume":"20","author":"Kawahara","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Detal C(T))","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/ng.2853","article-title":"Therapeutic modulation of eIF2alpha phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models","volume":"46","author":"Kim","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.freeradbiomed.2013.01.003","article-title":"Oxidative damage to macromolecules in human Parkinson disease and the rotenone model","volume":"62","author":"Sanders","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s12035-014-9001-5","article-title":"Endoplasmic Reticulum Stress Plays a Key Role in Rotenone-Induced Apoptotic Death of Neurons","volume":"53","author":"Goswami","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5616","DOI":"10.1167\/iovs.14-14371","article-title":"The mitochondrial complex I inhibitor rotenone induces endoplasmic reticulum stress and activation of GSK-3beta in cultured rat retinal cells","volume":"55","author":"Han","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"280","DOI":"10.14348\/molcells.2017.2320","article-title":"Neuroprotective Effects of Protein Tyrosine Phosphatase 1B Inhibition against ER Stress-Induced Toxicity","volume":"40","author":"Jeon","year":"2017","journal-title":"Mol. Cells"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"10756","DOI":"10.1523\/JNEUROSCI.23-34-10756.2003","article-title":"Mechanism of toxicity in rotenone models of Parkinson\u2019s disease","volume":"23","author":"Sherer","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"104352","DOI":"10.1016\/j.nbd.2018.12.012","article-title":"Chronic stress-induced gut dysfunction exacerbates Parkinson\u2019s disease phenotype and pathology in a rotenone-induced mouse model of Parkinson\u2019s disease","volume":"135","author":"Dodiya","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"8516","DOI":"10.1074\/jbc.M210432200","article-title":"Mitochondrial Complex I Inhibitor Rotenone Induces Apoptosis through Enhancing Mitochondrial Reactive Oxygen Species Production","volume":"278","author":"Li","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1083\/jcb.201009132","article-title":"Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson\u2019s disease model","volume":"192","author":"Choi","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.bcp.2008.04.010","article-title":"GSK3beta and endoplasmic reticulum stress mediate rotenone-induced death of SK-N-MC neuroblastoma cells","volume":"76","author":"Chen","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1021\/acs.chemrestox.6b00181","article-title":"Activating Transcription Factor 4 (ATF4)-ATF3-C\/EBP Homologous Protein (CHOP) Cascade Shows an Essential Role in the ER Stress-Induced Sensitization of Tetrachlorobenzoquinone-Challenged PC12 Cells to ROS-Mediated Apoptosis via Death Receptor 5 (DR5) Signaling","volume":"29","author":"Liu","year":"2016","journal-title":"Chem. Res. Toxicol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1159\/000362974","article-title":"Down-regulation of PERK-ATF4-CHOP pathway by Astragaloside IV is associated with the inhibition of endoplasmic reticulum stress-induced podocyte apoptosis in diabetic rats","volume":"33","author":"Chen","year":"2014","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s11010-011-1211-9","article-title":"Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK\/ATF4\/CHOP signaling pathway","volume":"364","author":"Cao","year":"2012","journal-title":"Mol. Cell. Biochem."},{"key":"ref_57","first-page":"953","article-title":"Detecting Cleaved Caspase-3 in Apoptotic Cells by Flow Cytometry","volume":"11","author":"Crowley","year":"2016","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ymthe.2016.10.013","article-title":"Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization","volume":"25","author":"Wang","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1002\/path.3969","article-title":"The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies","volume":"226","author":"Nijholt","year":"2012","journal-title":"J. Pathol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.2353\/ajpath.2009.080814","article-title":"The unfolded protein response is activated in pretangle neurons in Alzheimer\u2019s disease hippocampus","volume":"174","author":"Hoozemans","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e1672","DOI":"10.1038\/cddis.2015.49","article-title":"Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity","volume":"6","author":"Halliday","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/s00401-015-1487-z","article-title":"PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia","volume":"130","author":"Radford","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4706","DOI":"10.1093\/hmg\/ddt319","article-title":"The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons","volume":"22","author":"Wang","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"10851","DOI":"10.1523\/JNEUROSCI.1630-10.2010","article-title":"Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice","volume":"30","author":"Xu","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1038\/s41374-019-0233-x","article-title":"Association between TDP-43 and mitochondria in inclusion body myositis","volume":"99","author":"Huntley","year":"2019","journal-title":"Lab. Investig."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1385\/JMN:17:2:205","article-title":"Dysregulation of cellular calcium homeostasis in Alzheimer\u2019s disease: Bad genes and bad habits","volume":"17","author":"Mattson","year":"2001","journal-title":"J. Mol. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.bbrc.2016.08.168","article-title":"Calcium and Parkinson\u2019s disease","volume":"483","author":"Surmeier","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.1073\/pnas.0409402102","article-title":"Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington\u2019s disease","volume":"102","author":"Tang","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"225","DOI":"10.3389\/fncel.2015.00225","article-title":"Calcium dysregulation links ALS defective proteins and motor neuron selective vulnerability","volume":"9","author":"Leal","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_70","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_71","doi-asserted-by":"crossref","first-page":"12093","DOI":"10.1523\/JNEUROSCI.2495-13.2014","article-title":"TDP-43 toxicity proceeds via calcium dysregulation and necrosis in aging Caenorhabditis elegans motor neurons","volume":"34","author":"Aggad","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/ni.1980","article-title":"Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome","volume":"12","author":"Nakahira","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/nri.2017.21","article-title":"Mitochondrial DNA in innate immune responses and inflammatory pathology","volume":"17","author":"West","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"615","DOI":"10.3389\/fimmu.2020.00615","article-title":"Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response","volume":"11","author":"Wan","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"613","DOI":"10.2174\/1570159X18666200123165002","article-title":"A New Vision of Mitochondrial Unfolded Protein Response to the Sirtuin Family","volume":"18","author":"Weng","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1080\/15548627.2019.1686729","article-title":"PTK2\/FAK regulates UPS impairment via SQSTM1\/p62 phosphorylation in TARDBP\/TDP-43 proteinopathies","volume":"16","author":"Lee","year":"2020","journal-title":"Autophagy"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1186\/s12974-020-01963-6","article-title":"The overexpression of TDP-43 in astrocytes causes neurodegeneration via a PTP1B-mediated inflammatory response","volume":"17","author":"Lee","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"406","DOI":"10.3389\/fphar.2019.00406","article-title":"Vitamin B12 Enhances Nerve Repair and Improves Functional Recovery After Traumatic Brain Injury by Inhibiting ER Stress-Induced Neuron Injury","volume":"10","author":"Wu","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.freeradbiomed.2009.04.023","article-title":"A novel role for vitamin B(12): Cobalamins are intracellular antioxidants in vitro","volume":"47","author":"Birch","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.ebiom.2019.11.026","article-title":"Human iPSC-derived astrocytes from ALS patients with mutated C9ORF72 show increased oxidative stress and neurotoxicity","volume":"50","author":"Birger","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1080\/15548627.2019.1644076","article-title":"ALS-FTLD-linked mutations of SQSTM1\/p62 disrupt selective autophagy and NFE2L2\/NRF2 anti-oxidative stress pathway","volume":"16","author":"Deng","year":"2020","journal-title":"Autophagy"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1002\/humu.21582","article-title":"Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death","volume":"32","author":"Angeles","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.freeradbiomed.2006.11.006","article-title":"Involvement of PI3K\/PKG\/ERK1\/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: Implications for Alzheimer\u2019s disease","volume":"42","author":"Abdul","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/s41594-020-00537-7","article-title":"TDP-43 aggregation induced by oxidative stress causes global mitochondrial imbalance in ALS","volume":"28","author":"Zuo","year":"2021","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/nature05292","article-title":"Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases","volume":"443","author":"Lin","year":"2006","journal-title":"Nature"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"16441","DOI":"10.1038\/s41598-017-16637-2","article-title":"Activation of the mitochondrial unfolded protein response promotes longevity and dopamine neuron survival in Parkinson\u2019s disease models","volume":"7","author":"Cooper","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"610","DOI":"10.2174\/1567205013666151221145445","article-title":"Evidence for Mitochondrial UPR Gene Activation in Familial and Sporadic Alzheimer\u2019s Disease","volume":"13","author":"Beck","year":"2016","journal-title":"Curr. Alzheimer Res."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/1\/82\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:55:30Z","timestamp":1760169330000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/1\/82"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,29]]},"references-count":87,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["antiox11010082"],"URL":"https:\/\/doi.org\/10.3390\/antiox11010082","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,29]]}}}