Genetic ablation of <i>Sarm1</i> attenuates expression and mislocalization of phosphorylated TDP-43 after mouse repetitive traumatic brain injury

作者全名："Dogan, Elif O.; Bouley, James; Zhong, Jianjun; Harkins, Ashley L.; Keeler, Allison M.; Bosco, Daryl A.; Brown Jr, Robert H.; Henninger, Nils"

作者地址："[Dogan, Elif O.; Bouley, James; Zhong, Jianjun; Harkins, Ashley L.; Bosco, Daryl A.; Brown Jr, Robert H.; Henninger, Nils] Univ Massachusetts, Dept Neurol, Chan Med Sch, 55 Lake Ave, Worcester, MA 01655 USA; [Zhong, Jianjun] Chongqing Med Univ, Dept Neurosurg, Affiliated Hosp 1, Chongqing, Peoples R China; [Harkins, Ashley L.] Univ Massachusetts, Morningside Grad Sch Biomed Sci, Grad Program Neurosci, Chan Med Sch, Worcester, MA 01655 USA; [Harkins, Ashley L.; Keeler, Allison M.] Univ Massachusetts, Chan Med Sch, Horae Gene Therapy Ctr, Worcester, MA 01605 USA; [Keeler, Allison M.] Univ Massachusetts, Dept Pediat, Chan Med Sch, Worcester, MA 01605 USA; [Keeler, Allison M.] Univ Massachusetts, NeuroNexus Inst, Chan Med Sch, Worcester, MA 01605 USA; [Henninger, Nils] Univ Massachusetts, Dept Psychiat, Chan Med Sch, 55 Lake Ave, Worcester, MA 01655 USA"

通信作者："Henninger, N (通讯作者)，Univ Massachusetts, Dept Neurol, Chan Med Sch, 55 Lake Ave, Worcester, MA 01655 USA.; Henninger, N (通讯作者)，Univ Massachusetts, Dept Psychiat, Chan Med Sch, 55 Lake Ave, Worcester, MA 01655 USA."

来源：ACTA NEUROPATHOLOGICA COMMUNICATIONS

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001130306600001

JCR分区：Q1

影响因子：6.2

年份：2023

卷号：11

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Axon; Behavior; Brain injury; Glial scar; Haploinsufficiency; Interleukin; Neurodegeneration; SARM1; Tau; TDP-43

摘要："Traumatic brain injury (TBI), particularly when moderate-to-severe and repetitive, is a strong environmental risk factor for several progressive neurodegenerative disorders. Mislocalization and deposition of transactive response DNA binding protein 43 (TDP-43) has been reported in both TBI and TBI-associated neurodegenerative diseases. It has been hypothesized that axonal pathology, an early event after TBI, may promote TDP-43 dysregulation and serve as a trigger for neurodegenerative processes. We sought to determine whether blocking the prodegenerative Sarm1 (sterile alpha and TIR motif containing 1) axon death pathway attenuates TDP-43 pathology after TBI. We subjected 111 male Sarm1 wild type, hemizygous, and knockout mice to moderate-to-severe repetitive TBI (rTBI) using a previously established injury paradigm. We conducted serial neurological assessments followed by histological analyses (NeuN, MBP, Iba-1, GFAP, pTDP-43, and AT8) at 1 month after rTBI. Genetic ablation of the Sarm1 gene attenuated the expression and mislocalization of phosphorylated TDP-43 (pTDP-43) and accumulation of pTau. In addition, Sarm1 knockout mice had significantly improved cortical neuronal and axonal integrity, functional deficits, and improved overall survival after rTBI. In contrast, removal of one Sarm1 allele delayed, but did not prevent, neurological deficits and neuroaxonal loss. Nevertheless, Sarm1 haploinsufficient mice showed significantly less microgliosis, pTDP-43 pathology, and pTau accumulation when compared to wild type mice. These data indicate that the Sarm1-mediated prodegenerative pathway contributes to pathogenesis in rTBI including the pathological accumulation of pTDP-43. This suggests that anti-Sarm1 therapeutics are a viable approach for preserving neurological function after moderate-to-severe rTBI."

基金机构：National Institute of Neurological Disorders and Stroke

基金资助正文：None.