Wong Jamie K, Roselle Anna K, Shue Taylor M, Shimshak Serena J E, Beaty Joseph M, Celestin Nadia M, Gao Ivy, Griffin Rose P, Cudkowicz Merit E, Sadiq Saud A
Larry G. Gluck Division of ALS Research, Tisch Multiple Sclerosis Research Center of New York, New York, NY 10019, USA.
Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Brain Commun. 2022 Aug 22;4(4):fcac207. doi: 10.1093/braincomms/fcac207. eCollection 2022.
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by motor neuron degeneration. Approximately 90% of cases occur sporadically with no known cause while 10% are familial cases arising from known inherited genetic mutations. studies have predominantly utilized transgenic models harbouring amyotrophic lateral sclerosis-associated gene mutations, which have not hitherto elucidated mechanisms underlying motor neuron death or identified therapeutic targets specific to sporadic amyotrophic lateral sclerosis. Here we provide evidence demonstrating pathogenic differences in CSF from patients with sporadic amyotrophic lateral sclerosis and familial amyotrophic lateral sclerosis patients with mutations in and . Using a novel CSF-mediated animal model, we show that intrathecal delivery of sporadic amyotrophic lateral sclerosis patient-derived CSF into the cervical subarachnoid space in adult wild-type mice induces permanent motor disability which is associated with hallmark pathological features of amyotrophic lateral sclerosis including motor neuron loss, cytoplasmic TDP-43 translocation, reactive astrogliosis and microglial activation. Motor impairments are not induced by SOD1, C9orf72 or TARDBP CSF, although a moderate degree of histopathological change occurs in C9orf72 and TARDBP CSF-injected mice. By conducting a series of CSF filtration studies and global proteomic analysis of CSF, we identified apolipoprotein B-100 in sporadic amyotrophic lateral sclerosis CSF as the putative agent responsible for inducing motor disability, motor neuron degeneration and pathological translocation of TDP-43. Apolipoprotein B-100 alone is sufficient to recapitulate clinical and pathological outcomes and induce death of human induced pluripotent stem cell-derived motor neurons . Targeted removal of apolipoprotein B-100 from sporadic amyotrophic lateral sclerosis CSF via filtration or immunodepletion successfully attenuated the neurotoxic capacity of sporadic amyotrophic lateral sclerosis CSF to induce motor disability, motor neuron death, and TDP-43 translocation. This study presents apolipoprotein B-100 as a novel therapeutic target specific for the predominant sporadic form of amyotrophic lateral sclerosis and establishes proof-of-concept to support CSF pheresis as a therapeutic strategy for mitigating neurotoxicity in sporadic amyotrophic lateral sclerosis.
肌萎缩侧索硬化症是一种致命的神经退行性疾病，其特征为运动神经元变性。约90%的病例为散发性，病因不明，而10%为家族性病例，由已知的遗传基因突变引起。此前的研究主要利用携带肌萎缩侧索硬化症相关基因突变的转基因模型，但这些研究尚未阐明运动神经元死亡的潜在机制，也未确定散发性肌萎缩侧索硬化症特有的治疗靶点。在此，我们提供证据表明，散发性肌萎缩侧索硬化症患者与携带[相关基因名称]突变的家族性肌萎缩侧索硬化症患者的脑脊液存在致病性差异。使用一种新型的脑脊液介导的动物模型，我们发现，将散发性肌萎缩侧索硬化症患者来源的脑脊液鞘内注射到成年野生型小鼠的颈段蛛网膜下腔会导致永久性运动功能障碍，这与肌萎缩侧索硬化症的标志性病理特征相关，包括运动神经元丢失、细胞质TDP-43易位、反应性星形胶质细胞增生和小胶质细胞激活。超氧化物歧化酶1（SOD1）、9号染色体开放阅读框72（C9orf72）或TAR DNA结合蛋白43（TARDBP）脑脊液不会诱导运动功能障碍，尽管在注射C9orf72和TARDBP脑脊液的小鼠中出现了中度程度的组织病理学变化。通过进行一系列脑脊液过滤研究和脑脊液的全蛋白质组分析，我们确定散发性肌萎缩侧索硬化症脑脊液中的载脂蛋白B-100是导致运动功能障碍、运动神经元变性和TDP-43病理易位的推定因子。单独的载脂蛋白B-100就足以重现临床和病理结果，并诱导人诱导多能干细胞来源的运动神经元死亡。通过过滤或免疫耗竭从散发性肌萎缩侧索硬化症脑脊液中靶向去除载脂蛋白B-100，成功减弱了散发性肌萎缩侧索硬化症脑脊液诱导运动功能障碍、运动神经元死亡和TDP-43易位的神经毒性能力。本研究提出载脂蛋白B-100是散发性肌萎缩侧索硬化症主要散发性形式特有的新型治疗靶点，并建立了概念验证，以支持脑脊液置换作为减轻散发性肌萎缩侧索硬化症神经毒性的治疗策略。
