JCI insightPub Date : 2026-04-02DOI: 10.1172/jci.insight.192155
Sarah A Wolfe, Yuliang Ma, Tomer M Yaron-Barir, Carly Chang, Caila A Pilo, Majid Ghassemian, Amanda J Roberts, Sang Ryeul Lee, Benjamin A Henson, Kristen Jepsen, Jared L Johnson, Lewis C Cantley, Susan S Taylor, George Gorrie, Alexandra C Newton
{"title":"Sex specific disruptions in PKCγ signaling in a mouse model of Spinocerebellar Ataxia Type 14.","authors":"Sarah A Wolfe, Yuliang Ma, Tomer M Yaron-Barir, Carly Chang, Caila A Pilo, Majid Ghassemian, Amanda J Roberts, Sang Ryeul Lee, Benjamin A Henson, Kristen Jepsen, Jared L Johnson, Lewis C Cantley, Susan S Taylor, George Gorrie, Alexandra C Newton","doi":"10.1172/jci.insight.192155","DOIUrl":"10.1172/jci.insight.192155","url":null,"abstract":"<p><p>Spinocerebellar Ataxia Type 14 (SCA14) is an autosomal dominant neurodegenerative disease caused by mutations in the gene encoding protein kinase C gamma (PKCγ), a Ca2+/diacylglycerol (DG)-dependent serine/threonine kinase dominantly expressed in cerebellar Purkinje cells. These mutations impair autoinhibitory constraints to increase the basal activity of the kinase, resulting in deficits in the cerebellum that are not observed upon simple deletion of the gene, and severe ataxia. To better understand the impact of aberrant PKCγ signaling in disease pathology, we developed a knock-in murine model of the SCA14 mutation ΔF48 in PKCγ. This fully-penetrant mutation is severe in humans and is mechanistically informative as it has high basal activity but is unresponsive to agonist stimulation. Genetic, behavioral, and molecular testing revealed that ΔF48 PKCγ mice have ataxia-related phenotypes and an altered cerebellar phosphoproteome driven primarily by enhanced Ca2+/calmodulin-dependent Kinase II (CaMKII) signaling, effects that were more severe in male mice. Analysis of existing human data revealed that SCA14 has a significantly earlier age of onset for males compared with females. Data from this clinically relevant mutation suggested that enhanced basal activity of PKCγ is sufficient to cause ataxia and that treatment strategies to modulate aberrant PKCγ may be particularly beneficial in males.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-04-02DOI: 10.1172/jci.insight.201466
Abhishek Jauhari, Adam C Monek, Olena S Abakumova, Tanisha Singh, Sukhman Singh, Xiaomin Wang, Carley S Clise, Diane L Carlisle, Robert M Friedlander
{"title":"Metabolic reprogramming is critical to microglial activation in Huntington's disease.","authors":"Abhishek Jauhari, Adam C Monek, Olena S Abakumova, Tanisha Singh, Sukhman Singh, Xiaomin Wang, Carley S Clise, Diane L Carlisle, Robert M Friedlander","doi":"10.1172/jci.insight.201466","DOIUrl":"https://doi.org/10.1172/jci.insight.201466","url":null,"abstract":"<p><p>Huntington's disease (HD) is a fatal neurodegenerative disease caused by an expanded polyglutamine (CAG) repeat in the N-terminal of the Huntingtin protein (HTT). Microglial activation and elevated pro-inflammatory cytokines are observed in HD brains, but the mechanisms regulating neuroinflammation and microglial activation are poorly understood. Metformin-mediated neuroprotection has been demonstrated in experimental models of neurodegeneration, including HD. We found that metformin inhibits mitochondrial DNA (mtDNA) release and subsequent neuroinflammation in the cortex and striatum of a mouse model of HD. Moreover, elevated pro-inflammatory cytokines and microglial activation are inhibited by metformin in HD transgenic mice brain. Metformin reduced pathological microglial clusters and shifted towards a quiescent, homeostatic phenotype. Metformin improved aberrant immunometabolism in HD mouse brain and primary microglia. Mechanistically found that metformin regulates mitochondrial fission, reprograms deregulated metabolism in HD microglia, and controls microglial activation and inflammation in HD transgenic mice.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-04-02DOI: 10.1172/jci.insight.202638
Gaurav Kumar, Nisita Chaihongsa, Daniel T Brozoski, Daria Golosova, Ibrahim Vazirabad, Ko-Ting Lu, Kelsey K Wackman, Ravi K Singh, Curt D Sigmund
{"title":"Vascular smooth muscle RbFox2 regulates the cytoskeleton and arterial stiffness by a RhoBTB1-Cullin-3 mechanism.","authors":"Gaurav Kumar, Nisita Chaihongsa, Daniel T Brozoski, Daria Golosova, Ibrahim Vazirabad, Ko-Ting Lu, Kelsey K Wackman, Ravi K Singh, Curt D Sigmund","doi":"10.1172/jci.insight.202638","DOIUrl":"https://doi.org/10.1172/jci.insight.202638","url":null,"abstract":"<p><p>The RhoBTB1-Cullin3 (CUL3) pathway in smooth muscle cells (SMCs) controls the ubiquitination and proteasomal degradation of target proteins that regulate vasodilation, vasoconstriction, and the actin cytoskeleton, and through this blood pressure (BP) and arterial stiffness. Using proximity labelling coupled with mass spectrometry in A7R5 SMCs, we identified proteins which bound to the C-terminal half of RhoBTB1 which functions as an adapter to deliver substrates to CUL3. We examined the physiological relevance of one of these substrates, RbFox2. Co-immunoprecipitation validated the interaction of RbFox2 with RhoBTB1. RbFox2 expression was elevated in response to inhibition of the ubiquitination-proteasomal pathway, CUL3-deficiency, and RhoBTB1 inhibition by either siRNA or angiotensin II (ANG). RbFox2 was ubiquitinated in a RhoBTB1- and CUL3-dependent manner suggesting its regulation through the RhoBTB1-CUL3-dependent ubiquitin-proteasome pathway. Inhibition of RbFox2 impaired the actin cytoskeleton in A7R5 cells and in primary SMC from RbFox2Flox/Flox (RbFox2F/F) mice and decreased the levels of globular and filamentous actin. ANG increased BP and arterial stiffness of RbFox2F/F mice, but the progression of arterial stiffness was halted after SMC-specific RbFox2 deletion despite a continued rise in BP. We conclude that RhoBTB1 and RbFox2 are important regulators of arterial stiffness through a mechanism that influences cytoskeletal integrity.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-04-02DOI: 10.1172/jci.insight.201949
William J Crisler, Noor Sohail, Samuel J Steuart, Maria Vazquez-Machado, Arjun Mahajan, Maureen Whittelsey, Alex Pickering, Michael J Martinez, Theresa Hutchins, Jessica E Teague, Qian Zhan, Shannan Ho Sui, Ruth Ann Vleugels, Kathryn S Torok, Heidi Jacobe, Rachael A Clark, Avery LaChance
{"title":"In morphea, cytotoxic resident memory T cells induce chronic, immunogenic endothelial cell injury via necroptosis.","authors":"William J Crisler, Noor Sohail, Samuel J Steuart, Maria Vazquez-Machado, Arjun Mahajan, Maureen Whittelsey, Alex Pickering, Michael J Martinez, Theresa Hutchins, Jessica E Teague, Qian Zhan, Shannan Ho Sui, Ruth Ann Vleugels, Kathryn S Torok, Heidi Jacobe, Rachael A Clark, Avery LaChance","doi":"10.1172/jci.insight.201949","DOIUrl":"https://doi.org/10.1172/jci.insight.201949","url":null,"abstract":"","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-03-31eCollection Date: 2026-05-08DOI: 10.1172/jci.insight.196665
Galina Gritsina, Sandip Kumar Rath, Hongshun Shi, Qi Chu, Wanqing Xie, Que Thanh Waning Nguyen, Sambhavi Senthil, Thomas J Myers, Mehmet A Bilen, Sarah E Fenton, Maha Hussain, David S Yu, Jonathan C Zhao, Jindan Yu
{"title":"AURKA inhibitor VIC-1911 induces mitotic defects and functional BRCAness, sensitizing prostate cancer to PARP inhibition.","authors":"Galina Gritsina, Sandip Kumar Rath, Hongshun Shi, Qi Chu, Wanqing Xie, Que Thanh Waning Nguyen, Sambhavi Senthil, Thomas J Myers, Mehmet A Bilen, Sarah E Fenton, Maha Hussain, David S Yu, Jonathan C Zhao, Jindan Yu","doi":"10.1172/jci.insight.196665","DOIUrl":"10.1172/jci.insight.196665","url":null,"abstract":"<p><p>VIC-1911 (formerly TAS-119) is a next-generation, ATP-competitive aurora kinase A (AURKA) inhibitor with a favorable biosafety profile. However, it has not been evaluated in prostate cancer (PCa), wherein AURKA is highly expressed in advanced stages and represents a critical therapeutic target. Here, we demonstrate that VIC-1911 potently inhibits AURKA activity with high selectivity over AURKB/C across diverse PCa cell lines. Treatment with VIC-1911, even at nanomolar concentrations, substantially inhibits the growth of both androgen receptor-positive (AR-positive) and AR-negative PCa cells. VIC-1911 triggers mitotic failure, induces DNA double-strand breaks (DSBs), and activates the p53 pathway, halting cell division and inducing cell death. Notably, VIC-1911 showed synergistic effects in inhibiting PCa cell growth in vitro and xenograft tumor growth in vivo with poly (ADP-ribose) polymerase inhibitors, which have proven effective in PCa with a deficiency in homologous recombination (HR) repair. Mechanistically, VIC-1911 disabled HR-mediated repair of DSBs in otherwise HR-proficient PCa cells, leading to a \"BRCAness\" phenotype and pronounced accumulation of DNA damage and mitotic catastrophe. In summary, our study uncovers what we believe is a novel mechanism to induce functional BRCAness through mitotic arrest and highlights VIC-1911 as a promising therapeutic agent for advanced PCa, either as a single agent or in combination, sensitizing HR-proficient tumors to PARP inhibitors.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-03-31DOI: 10.1172/jci.insight.205174
Anna J Son, Emmanuel Rapp, Alex Wiezorek, Max G Leung, Ronadip R Banerjee, Thomas H Leung
{"title":"Cycling GLP-1 receptor agonist treatment induces therapeutic resistance and increased adiposity.","authors":"Anna J Son, Emmanuel Rapp, Alex Wiezorek, Max G Leung, Ronadip R Banerjee, Thomas H Leung","doi":"10.1172/jci.insight.205174","DOIUrl":"https://doi.org/10.1172/jci.insight.205174","url":null,"abstract":"","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-03-31DOI: 10.1172/jci.insight.198360
Huidong Shi, Zhi-Chun Ding, Ogacheko D Okoko, Xin Wang, George Zhou, Yan Ye, Md Yeashin Gazi, Caitlin Brandle, Lirong Pei, Rafal Pacholczyk, Catherine C Hedrick, Locke J Bryan, Gang Zhou
{"title":"Chemotherapy-induced reactive myelopoiesis promotes expansion of immunosuppressive neutrophil-like monocytes in mice and humans.","authors":"Huidong Shi, Zhi-Chun Ding, Ogacheko D Okoko, Xin Wang, George Zhou, Yan Ye, Md Yeashin Gazi, Caitlin Brandle, Lirong Pei, Rafal Pacholczyk, Catherine C Hedrick, Locke J Bryan, Gang Zhou","doi":"10.1172/jci.insight.198360","DOIUrl":"10.1172/jci.insight.198360","url":null,"abstract":"<p><p>Cytotoxic chemotherapy primarily targets rapidly proliferating cancer cells but also depletes normal myeloid cells. The resulting cell loss triggers reactive myelopoiesis, a compensatory process in which hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) regenerate myeloid lineages. We previously showed that the alkylating agent cyclophosphamide (CTX) induces myelopoiesis leading to the expansion of immunosuppressive monocytes in mice. However, the molecular features and clinical relevance of these cells remain poorly understood. Here, we report the emergence of immunosuppressive monocytes in the peripheral blood of lymphoma patients receiving CTX-containing chemotherapy. To gain mechanistic insight into CTX-induced myelopoiesis, we performed single-cell RNA sequencing (scRNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on BM monocytes from CTX-treated mice. These analyses revealed a heterogeneous monocyte population and demonstrated that CTX skews myelopoiesis toward the generation of neutrophil-like monocytes (NeuMo). Moreover, CTX-induced NeuMo cells, enriched within the CXCR4⁺CX3CR1⁻ monocyte subset, exhibited potent T-cell suppressive activity. Using the NeuMo gene signature, reanalysis of public scRNA-seq datasets identified a transcriptionally similar monocyte subset in chemotherapy-treated cancer patients. Collectively, our findings suggest that the expansion of NeuMo-like cells following chemotherapy represents a conserved immunoregulatory feedback mechanism with potential impact on tumor response to chemoimmunotherapy.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-03-31DOI: 10.1172/jci.insight.195329
Jacqueline Plesset, Meredith L Stone, John C McVey, Heather Coho, Kelly Markowitz, Kayjana Coho, Jesse Lee, Anna S Thickens, Devora Delman, Gregory L Beatty
{"title":"TLR2 signaling regulates T cell exclusion in pancreatic ductal adenocarcinoma.","authors":"Jacqueline Plesset, Meredith L Stone, John C McVey, Heather Coho, Kelly Markowitz, Kayjana Coho, Jesse Lee, Anna S Thickens, Devora Delman, Gregory L Beatty","doi":"10.1172/jci.insight.195329","DOIUrl":"10.1172/jci.insight.195329","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) shows profound resistance to immunotherapy due to its immunosuppressive tumor microenvironment. Here, we studied the relationship between T cell infiltration and innate immune signaling in PDAC, identifying Toll-like receptor 2 (TLR2) as a key regulator of T cell exclusion. TLR2 expression correlated with T cell infiltration in both human and mouse PDAC tumors. Using genetic knockout models and adoptive T cell transfer experiments, we found that TLR2 expression in both T cells and non-T cells contributes to T cell exclusion in PDAC. Notably, successful infiltration of adoptively transferred tumor-specific T cells required TLR2 deletion in both the transferred cells and the recipient host. The therapeutic implications of these findings are demonstrated through both genetic deletion and pharmacological inhibition of TLR2 using AAV-mediated and antibody-based approaches in murine models, resulting in decreased tumor growth and extended survival. Collectively, these findings identify TLR2 as a key modulator of T cell trafficking and immune suppression within the PDAC microenvironment, suggesting its potential as a therapeutic target for improving treatment outcomes.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147616087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-03-26DOI: 10.1172/jci.insight.198032
Yanna Tian, D Stephen Serafin, Monserrat Avila-Zozaya, Alyssa M Tauro, Natalie M Torres-Valle, Bryan M Kistner, Danielle M Dy, Elizabeth S Douglas, Kathleen M Caron
{"title":"Beta-arrestin 1/2 are essential for embryonic lymphatic vessel development.","authors":"Yanna Tian, D Stephen Serafin, Monserrat Avila-Zozaya, Alyssa M Tauro, Natalie M Torres-Valle, Bryan M Kistner, Danielle M Dy, Elizabeth S Douglas, Kathleen M Caron","doi":"10.1172/jci.insight.198032","DOIUrl":"https://doi.org/10.1172/jci.insight.198032","url":null,"abstract":"<p><p>β-arrestins are ubiquitously expressed cytosolic adaptor proteins that regulate G protein-coupled receptor-dependent and -independent pathways essential for numerous physiological functions. This study investigated the role of β-arrestin1 and -2 in embryonic lymphatic vessel development and survival by generating and characterizing mice with lymphatic, tamoxifen-inducible loss of the genes encoding β-arrestin-1 and -2 (Arrb1/2ΔiLEC). At embryonic day15.5 (E15.5), Arrb1/2ΔiLEC embryos exhibit profound hydrops fetalis and increased embryonic mortality compared to control Arrb1/2fl/fl embryos. Edematous Arrb1/2ΔiLEC embryos, which were more often represented by the female sex, showed growth restriction and decreased lymphatic endothelial cell (LEC) proliferation in the jugular lymphatic sac compared to controls. In vitro knockdown of β-arrestin1 in LECs increased proliferation and increased activation of AKT, while knockdown of β-arrestin2 decreased proliferation and decreased activation of both ERK and CREB. Arrb1/2ΔiLEC embryos also exhibited dilated dermal lymphatics with decreased continuous VE-Cadherin adherens junctions compared to controls. These results were recapitulated in vitro in β-arrestin1 and/or -2 knockdown human LECs, which showed a decrease in membrane VE-Cadherin and β-catenin levels, and prevention of adrenomedullin-induced linearization of VE-cadherin at endothelial cell-cell junctions. Collectively, these results demonstrate that loss of β-arrestin1/2 in lymphatics causes hydrops fetalis, mid-gestational growth arrest and embryonic demise associated with reduced LEC proliferation and disrupted VE-Cadherin adherens junctions.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147512254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2026-03-26DOI: 10.1172/jci.insight.197941
Tetsuya Akiyama, Yi Zeng, Caiwei Guo, Olivia Gautier, Lauren Koepke, Heankel Lyons, Elana Molotsky, Juliane S Bombosch, Odilia Sianto, Jay P Ross, Phuong Hoang, Luke Zhao, Cole Spencer, Charlotte J Sumner, Michelle Monje, John W Day, Aaron D Gitler
{"title":"KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS.","authors":"Tetsuya Akiyama, Yi Zeng, Caiwei Guo, Olivia Gautier, Lauren Koepke, Heankel Lyons, Elana Molotsky, Juliane S Bombosch, Odilia Sianto, Jay P Ross, Phuong Hoang, Luke Zhao, Cole Spencer, Charlotte J Sumner, Michelle Monje, John W Day, Aaron D Gitler","doi":"10.1172/jci.insight.197941","DOIUrl":"10.1172/jci.insight.197941","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene leading to decreased SMN protein levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. SMN deficiency resulted in downregulation of kinesin heavy chain isoform 5A (KIF5A) in human neurons and in a mouse model of SMA. SMN associated with KIF5A mRNA and contributed to its stability. Reduced SMN levels impaired axon regeneration, which was rescued by KIF5A overexpression. Because KIF5A has also been connected to ALS, these findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as an SMN regulated factor. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147512223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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