{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T06:04:50Z","timestamp":1771308290666,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:00:00Z","timestamp":1770940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"U.S. Department of Defense","award":["AD1208694"],"award-info":[{"award-number":["AD1208694"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Peroxisome-proliferator\u2013activated receptor delta (PPAR\u03b4) regulates metabolic, mitochondrial, and inflammatory pathways implicated in neurodegeneration, making it an attractive therapeutic target for amyotrophic lateral sclerosis (ALS). In this study, we evaluated two PPAR\u03b4 agonists, KD3010 and T3D-959, in two established ALS\/FTD mouse models: an AAV-mediated C9orf72 G4C2-repeat expansion model (C9-149R) and the TDP-43Q331K transgenic model. Drug treatment was initiated prior to the emergence of key disease features and continued for 9\u201310 months. Comprehensive behavioral, neuropathological, and biomarker analyses revealed marked differences between the two models. C9-149R mice exhibited reduced body weight and subtle behavioral alterations without robust motor deficits, whereas TDP-43Q331K mice developed pronounced, progressive motor and cognitive impairments accompanied by a ~7-fold elevation in plasma neurofilament light chain (NfL). Despite effective target engagement\u2014particularly for T3D-959\u2014neither PPAR\u03b4 agonist improved motor performance, cognitive behavior, neuroanatomical measures, plasma NfL levels, or disease-associated molecular phenotypes in either model. Prolonged KD3010 treatment resulted in loss of target engagement, consistent with drug tolerance, while T3D-959 sustained PPAR\u03b4 activation without therapeutic benefit. Together, these findings demonstrate that PPAR\u03b4 agonism is insufficient to modify disease progression in these ALS\/FTD mouse models and underscore the importance of publishing well-powered negative preclinical studies to refine therapeutic strategies for ALS.<\/jats:p>","DOI":"10.3390\/ijms27041820","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T17:51:32Z","timestamp":1771005092000},"page":"1820","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PPAR-Delta Agonist Therapies Did Not Rescue Hallmark Disease Phenotypes in Two Sets of Preclinical Trials in ALS TDP-43 and C9orf72 Model Mice"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0880-6160","authenticated-orcid":false,"given":"David T.","family":"Luong","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenchen","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eunice","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3404-4402","authenticated-orcid":false,"given":"Nolan","family":"Tanji","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5104-7615","authenticated-orcid":false,"given":"Ivy","family":"Duong","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4610-9404","authenticated-orcid":false,"given":"Brandon","family":"Galero","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9900-4313","authenticated-orcid":false,"given":"Yong-Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5847-1687","authenticated-orcid":false,"given":"Craig L.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697, USA"},{"name":"UCI Center for Neurotherapeutics, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert R.","family":"La Spada","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697, USA"},{"name":"UCI Center for Neurotherapeutics, University of California, Irvine, CA 92697, USA"},{"name":"Department of Neurology, University of California, Irvine, CA 92697, USA"},{"name":"Department of Biological Chemistry, University of California, Irvine, CA 92697, USA"},{"name":"Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1056\/NEJMra1603471","article-title":"Amyotrophic Lateral Sclerosis","volume":"377","author":"Brown","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/j.1755-5949.2009.00116.x","article-title":"A Review of the Neural Mechanisms of Action and Clinical Efficiency of Riluzole in Treating Amyotrophic Lateral Sclerosis: What have we Learned in the Last Decade?","volume":"17","author":"Bellingham","year":"2011","journal-title":"CNS Neurosci. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1080\/21678421.2017.1353101","article-title":"Edaravone and its clinical development for amyotrophic lateral sclerosis","volume":"18","author":"Takei","year":"2017","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"17071","DOI":"10.1038\/nrdp.2017.71","article-title":"Amyotrophic lateral sclerosis","volume":"3","author":"Hardiman","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.expneurol.2015.09.019","article-title":"Excitotoxicity in ALS: Overstimulation, or overreaction?","volume":"275","author":"King","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/14737175.2023.2174018","article-title":"An evaluation of the combination of sodium phenylbutyrate and taurursodiol for the treatment of amyotrophic lateral sclerosis","volume":"23","author":"Sun","year":"2023","journal-title":"Expert. Rev. Neurother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","article-title":"Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS","volume":"72","author":"Mackenzie","year":"2011","journal-title":"Neuron"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1093\/brain\/aws004","article-title":"Characterization of frontotemporal dementia and\/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72","volume":"135","author":"Boeve","year":"2012","journal-title":"Brain"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1073\/pnas.1013343108","article-title":"Non-ATG-initiated translation directed by microsatellite expansions","volume":"108","author":"Zu","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1126\/science.aaw9157","article-title":"The nucleolus functions as a phase-separated protein quality control compartment","volume":"365","author":"Frottin","year":"2019","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1126\/science.1254917","article-title":"Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells","volume":"345","author":"Kwon","year":"2014","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.neuron.2016.04.005","article-title":"C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS\/FTD","volume":"90","author":"Liu","year":"2016","journal-title":"Neuron"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.neuron.2020.08.009","article-title":"Absence of Survival and Motor Deficits in 500 Repeat C9ORF72 BAC Mice","volume":"108","author":"Mordes","year":"2020","journal-title":"Neuron"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.neuron.2016.04.006","article-title":"Gain of Toxicity from ALS\/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs","volume":"90","author":"Jiang","year":"2016","journal-title":"Neuron"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13024-019-0310-z","article-title":"Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy","volume":"14","author":"Chew","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature20413","article-title":"Decoding ALS: From genes to mechanism","volume":"539","author":"Taylor","year":"2016","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.nbd.2005.06.005","article-title":"Coincident thresholds of mutant protein for paralytic disease and protein aggregation caused by restrictively expressed superoxide dismutase cDNA","volume":"20","author":"Wang","year":"2005","journal-title":"Neurobiol. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"E736","DOI":"10.1073\/pnas.1222809110","article-title":"ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43","volume":"110","author":"Arnold","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/nm.4003","article-title":"PPAR-delta is repressed in Huntington\u2019s disease, is required for normal neuronal function and can be targeted therapeutically","volume":"22","author":"Dickey","year":"2016","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"eaal2332","DOI":"10.1126\/scitranslmed.aal2332","article-title":"PPARdelta activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis","volume":"9","author":"Dickey","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_21","first-page":"238","article-title":"Targeting Alzheimer\u2019s Disease Neuro-Metabolic Dysfunction with a Small Molecule Nuclear Receptor Agonist (T3D-959) Reverses Disease Pathologies","volume":"6","author":"Tong","year":"2016","journal-title":"J Alzheimers Dis. Park."},{"key":"ref_22","first-page":"849","article-title":"Improved Brain Insulin\/IGF Signaling and Reduced Neuroinflammation with T3D-959 in an Experimental Model of Sporadic Alzheimer\u2019s Disease","volume":"55","author":"Tong","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.dnarep.2012.10.006","article-title":"Tissue-specific mismatch repair protein expression: MSH3 is higher than MSH6 in multiple mouse tissues","volume":"12","author":"Tome","year":"2013","journal-title":"DNA Repair"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.3233\/JAD-190864","article-title":"An Exploratory Phase IIa Study of the PPAR delta\/gamma Agonist T3D-959 Assessing Metabolic and Cognitive Function in Subjects with Mild to Moderate Alzheimer\u2019s Disease","volume":"73","author":"Chamberlain","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"ref_25","first-page":"1787","article-title":"A simple composite phenotype scoring system for evaluating mouse models of cerebellar ataxia","volume":"39","author":"Guyenet","year":"2010","journal-title":"J. Vis. Exp."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"fcab274","DOI":"10.1093\/braincomms\/fcab274","article-title":"Teaching an old dog new tricks: Serum troponin T as a biomarker in amyotrophic lateral sclerosis","volume":"3","author":"Radermacher","year":"2021","journal-title":"Brain Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"eabb3774","DOI":"10.1126\/scitranslmed.abb3774","article-title":"C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy","volume":"12","author":"Cook","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.tem.2008.09.002","article-title":"Adipogenesis and WNT signalling","volume":"20","author":"Christodoulides","year":"2009","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_29","first-page":"348765","article-title":"Genetic rodent models of amyotrophic lateral sclerosis","volume":"2011","year":"2011","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/0471141755.ph0567s69","article-title":"Rodent Models of Amyotrophic Lateral Sclerosis","volume":"69","author":"Philips","year":"2015","journal-title":"Curr. Protoc. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12","DOI":"10.15171\/apb.2019.003","article-title":"Crosstalk between Peroxisome Proliferator-Activated Receptors and Toll-Like Receptors: A Systematic Review","volume":"9","author":"Dana","year":"2019","journal-title":"Adv. Pharm. Bull."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Liu, Y., Colby, J.K., Zuo, X., Jaoude, J., Wei, D., and Shureiqi, I. (2018). The Role of PPAR-delta in Metabolism, Inflammation, and Cancer: Many Characters of a Critical Transcription Factor. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113339"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"34411","DOI":"10.1074\/jbc.M403058200","article-title":"The direct peroxisome proliferator-activated receptor target fasting-induced adipose factor (FIAF\/PGAR\/ANGPTL4) is present in blood plasma as a truncated protein that is increased by fenofibrate treatment","volume":"279","author":"Mandard","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Porcuna, J., Minguez-Martinez, J., and Ricote, M. (2021). The PPARalpha and PPARgamma Epigenetic Landscape in Cancer and Immune and Metabolic Disorders. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910573"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1820\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T05:12:49Z","timestamp":1771305169000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1820"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,13]]},"references-count":34,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27041820"],"URL":"https:\/\/doi.org\/10.3390\/ijms27041820","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,13]]}}}