Kelsey L. Krus , Ana Morales Benitez , Amy Strickland , Jeffrey Milbrandt , A. Joseph Bloom , Aaron DiAntonio
{"title":"肌萎缩性脊髓侧索硬化症的两个主要特征,即 STMN2 减少和致病性 TDP-43 协同作用,加速了小鼠运动能力的衰退。","authors":"Kelsey L. Krus , Ana Morales Benitez , Amy Strickland , Jeffrey Milbrandt , A. Joseph Bloom , Aaron DiAntonio","doi":"10.1016/j.expneurol.2024.115068","DOIUrl":null,"url":null,"abstract":"<div><div>Pathological TDP-43 loss from the nucleus and cytoplasmic aggregation occurs in almost all cases of ALS and half of frontotemporal dementia patients. <em>Stathmin2</em> (<em>Stmn2)</em> is a key target of TDP-43 regulation and aberrantly spliced <em>Stmn2</em> mRNA is found in patients with ALS, frontotemporal dementia, and Alzheimer's Disease. STMN2 participates in the axon injury response and its depletion <em>in vivo</em> partially replicates ALS-like symptoms including progressive motor deficits and distal NMJ denervation. The interaction between STMN2 loss and TDP-43 dysfunction has not been studied in mice because TDP-43 regulates human but not murine <em>Stmn2</em> splicing. Therefore, we generated trans-heterozygous mice that lack one functional copy of <em>Stmn2</em> and express one mutant TDP-43<sup>Q331K</sup> knock-in allele to investigate whether reduced STMN2 function exacerbates TDP-43-dependent pathology. Indeed, we observe synergy between these two alleles, resulting in an early onset, progressive motor deficit. Surprisingly, this behavioral defect is not accompanied by detectable neuropathology in the brain, spinal cord, peripheral nerves or at neuromuscular junctions (NMJs). However, the trans-heterozygous mice exhibit abnormal mitochondrial morphology in their distal axons and NMJs. As both STMN2 and TDP-43 affect mitochondrial dynamics, and neuronal mitochondrial dysfunction is a cardinal feature of many neurodegenerative diseases, this abnormality likely contributes to the observed motor deficit. These findings demonstrate that partial loss of STMN2 significantly exacerbates TDP-43-associated phenotypes, suggesting that STMN2 restoration could ameliorate TDP-43 related disease before the onset of degeneration.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"384 ","pages":"Article 115068"},"PeriodicalIF":4.6000,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Two cardinal features of ALS, reduced STMN2 and pathogenic TDP-43, synergize to accelerate motor decline in mice\",\"authors\":\"Kelsey L. Krus , Ana Morales Benitez , Amy Strickland , Jeffrey Milbrandt , A. Joseph Bloom , Aaron DiAntonio\",\"doi\":\"10.1016/j.expneurol.2024.115068\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Pathological TDP-43 loss from the nucleus and cytoplasmic aggregation occurs in almost all cases of ALS and half of frontotemporal dementia patients. <em>Stathmin2</em> (<em>Stmn2)</em> is a key target of TDP-43 regulation and aberrantly spliced <em>Stmn2</em> mRNA is found in patients with ALS, frontotemporal dementia, and Alzheimer's Disease. STMN2 participates in the axon injury response and its depletion <em>in vivo</em> partially replicates ALS-like symptoms including progressive motor deficits and distal NMJ denervation. The interaction between STMN2 loss and TDP-43 dysfunction has not been studied in mice because TDP-43 regulates human but not murine <em>Stmn2</em> splicing. Therefore, we generated trans-heterozygous mice that lack one functional copy of <em>Stmn2</em> and express one mutant TDP-43<sup>Q331K</sup> knock-in allele to investigate whether reduced STMN2 function exacerbates TDP-43-dependent pathology. Indeed, we observe synergy between these two alleles, resulting in an early onset, progressive motor deficit. Surprisingly, this behavioral defect is not accompanied by detectable neuropathology in the brain, spinal cord, peripheral nerves or at neuromuscular junctions (NMJs). However, the trans-heterozygous mice exhibit abnormal mitochondrial morphology in their distal axons and NMJs. As both STMN2 and TDP-43 affect mitochondrial dynamics, and neuronal mitochondrial dysfunction is a cardinal feature of many neurodegenerative diseases, this abnormality likely contributes to the observed motor deficit. These findings demonstrate that partial loss of STMN2 significantly exacerbates TDP-43-associated phenotypes, suggesting that STMN2 restoration could ameliorate TDP-43 related disease before the onset of degeneration.</div></div>\",\"PeriodicalId\":12246,\"journal\":{\"name\":\"Experimental Neurology\",\"volume\":\"384 \",\"pages\":\"Article 115068\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-11-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0014488624003947\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Neurology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014488624003947","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Two cardinal features of ALS, reduced STMN2 and pathogenic TDP-43, synergize to accelerate motor decline in mice
Pathological TDP-43 loss from the nucleus and cytoplasmic aggregation occurs in almost all cases of ALS and half of frontotemporal dementia patients. Stathmin2 (Stmn2) is a key target of TDP-43 regulation and aberrantly spliced Stmn2 mRNA is found in patients with ALS, frontotemporal dementia, and Alzheimer's Disease. STMN2 participates in the axon injury response and its depletion in vivo partially replicates ALS-like symptoms including progressive motor deficits and distal NMJ denervation. The interaction between STMN2 loss and TDP-43 dysfunction has not been studied in mice because TDP-43 regulates human but not murine Stmn2 splicing. Therefore, we generated trans-heterozygous mice that lack one functional copy of Stmn2 and express one mutant TDP-43Q331K knock-in allele to investigate whether reduced STMN2 function exacerbates TDP-43-dependent pathology. Indeed, we observe synergy between these two alleles, resulting in an early onset, progressive motor deficit. Surprisingly, this behavioral defect is not accompanied by detectable neuropathology in the brain, spinal cord, peripheral nerves or at neuromuscular junctions (NMJs). However, the trans-heterozygous mice exhibit abnormal mitochondrial morphology in their distal axons and NMJs. As both STMN2 and TDP-43 affect mitochondrial dynamics, and neuronal mitochondrial dysfunction is a cardinal feature of many neurodegenerative diseases, this abnormality likely contributes to the observed motor deficit. These findings demonstrate that partial loss of STMN2 significantly exacerbates TDP-43-associated phenotypes, suggesting that STMN2 restoration could ameliorate TDP-43 related disease before the onset of degeneration.
期刊介绍:
Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.