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SMA is characterized by degeneration of the spinal cord motor neurons caused by chronic low levels of survival motor neuron (SMN) protein. Prevention or slowing of neurodegeneration has been shown to ameliorate SMA disease severity. Significant progress has been made to develop SMN-dependent treatments that increase SMN levels. However, there is an unmet need to develop alternative therapeutic methods that are SMN-independent. The c-Jun-NH2 terminal kinase (JNK) signalling pathway mediates motor neuron degeneration in SMA. Genetic inactivation of the neuron-specific isoform, JNK3, ameliorates the disease phenotype in SMA mice without affecting SMN protein levels, indicating that JNK3 may represent a promising SMN-independent target for pharmacological intervention. We report that pharmacological inhibition of JNK using novel drug compounds based on three distinct chemical scaffolds, Anthrapyrazolone, Pyrimidinyl, and Pyridopyrimidine, prevents degeneration of SMN-deficient in vitro cultured primary cerebellum neurons and the spinal cord motor neurons derived from SMA mice. Furthermore, in vivo treatment with JNK inhibitors leads to a systemic improvement in the disease phenotype, promoting enhanced overall growth, including increased body weight and extended postnatal growth, alongside improved gross motor functions such as righting reflexes and the ability to walk until the later stages of survival. Notably, it also results in a significant and sustained increase in the lifespan of both male and female SMA mice. The sex-based analysis reveals male- and female-specific improvements that depend on the type and efficacy of inhibitors targeting distinct JNK isoforms. Importantly, treatment with JNK inhibitors did not affect SMN levels in the spinal cord or skeletal muscle, indicating that the observed rescue of the SMA phenotype occurs independently of SMN restoration. Collectively, these findings suggest that pharmacological inhibition of JNK may serve as a therapeutic strategy to prevent neurodegeneration, either in combination with SMN-enhancing approaches for treating severe forms of SMA, or as a stand-alone, SMN-independent intervention for moderate and mild SMA cases.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag111","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T12:45:41Z","timestamp":1774442741000},"source":"Crossref","is-referenced-by-count":0,"title":["Survival motor neuron protein-independent amelioration of spinal muscular atrophy by pharmacological inhibition of c-Jun-NH2 terminal kinase"],"prefix":"10.1093","volume":"8","author":[{"given":"Annapoorna","family":"Kannan","sequence":"first","affiliation":[{"name":"Center for Human Genetics, University of Oxford , Oxford OX3 7BN ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kanchan","family":"Bhatia","sequence":"additional","affiliation":[{"name":"School of Mathematical and Natural Sciences, NCIAS, Arizona State University , Glendale, AZ 85306 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoting","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Immunology, Houston Methodist Research Institute , Houston, TX 77030 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia","family":"Lesnik","sequence":"additional","affiliation":[{"name":"Bond Life Sciences Center, University of Missouri , Columbia, MO 65211 ,","place":["USA"]},{"name":"Department of Pathobiology and Integrative Biomedical Sciences, University of Missouri , Columbia, MO 65211 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabahat B","family":"Asad","sequence":"additional","affiliation":[{"name":"Bond Life Sciences Center, University of Missouri , Columbia, MO 65211 ,","place":["USA"]},{"name":"Department of Pathobiology and Integrative Biomedical Sciences, University of Missouri , Columbia, MO 65211 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kailyn","family":"Fiocca","sequence":"additional","affiliation":[{"name":"Hunt School of Dental Medicine, Texas Tech University Health Sciences Center El Paso , El Paso, TX 79905 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saif","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Barrow Neurological Institute, St.Joseph\u2019s Hospital and Medical Center, Dignity Health , Phoenix, AZ 85013 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yangbo","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami , Miami, FL 33136 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana","family":"Branzei","sequence":"additional","affiliation":[{"name":"The AIRC Institute of Molecular Oncology Foundation, IFOM ETS , Milan 20139 ,","place":["Italy"]},{"name":"University of Duisburg-Essen, Research Center One Health Ruhr, University Alliance Ruhr , , Essen 45141 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8575-9937","authenticated-orcid":false,"given":"Laxman","family":"Gangwani","sequence":"additional","affiliation":[{"name":"Bond Life Sciences Center, University of Missouri , Columbia, MO 65211 ,","place":["USA"]},{"name":"Department of Pathobiology and Integrative Biomedical Sciences, University of Missouri , Columbia, MO 65211 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