Department of Basic and Clinical Neuroscience, The Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, SE5 9RT, UK.
West China School of Medicine, West China Hospital, Sichuan University, Chengdu, China.
Acta Neuropathol Commun. 2019 Oct 28;7(1):166. doi: 10.1186/s40478-019-0800-9.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition that primarily affects the motor system and shares many features with frontotemporal dementia (FTD). Evidence suggests that ALS is a 'dying-back' disease, with peripheral denervation and axonal degeneration occurring before loss of motor neuron cell bodies. Distal to a nerve injury, a similar pattern of axonal degeneration can be seen, which is mediated by an active axon destruction mechanism called Wallerian degeneration. Sterile alpha and TIR motif-containing 1 (Sarm1) is a key gene in the Wallerian pathway and its deletion provides long-term protection against both Wallerian degeneration and Wallerian-like, non-injury induced axonopathy, a retrograde degenerative process that occurs in many neurodegenerative diseases where axonal transport is impaired. Here, we explored whether Sarm1 signalling could be a therapeutic target for ALS by deleting Sarm1 from a mouse model of ALS-FTD, a TDP-43, YFP-H double transgenic mouse. Sarm1 deletion attenuated motor axon degeneration and neuromuscular junction denervation. Motor neuron cell bodies were also significantly protected. Deletion of Sarm1 also attenuated loss of layer V pyramidal neuronal dendritic spines in the primary motor cortex. Structural MRI identified the entorhinal cortex as the most significantly atrophic region, and histological studies confirmed a greater loss of neurons in the entorhinal cortex than in the motor cortex, suggesting a prominent FTD-like pattern of neurodegeneration in this transgenic mouse model. Despite the reduction in neuronal degeneration, Sarm1 deletion did not attenuate age-related behavioural deficits caused by TDP-43. However, Sarm1 deletion was associated with a significant increase in the viability of male TDP-43 mice, suggesting a detrimental role of Wallerian-like pathways in the earliest stages of TDP-43-mediated neurodegeneration. Collectively, these results indicate that anti-SARM1 strategies have therapeutic potential in ALS-FTD.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，主要影响运动系统，与额颞叶痴呆（FTD）有许多共同特征。有证据表明，ALS 是一种“退行性”疾病，在外周神经失神经支配和轴突变性发生之前，运动神经元细胞体就已经丢失。在神经损伤的远端，可以看到类似的轴突变性模式，这是一种由称为沃勒变性的主动轴突破坏机制介导的。无菌α和 TIR 基序包含蛋白 1（Sarm1）是沃勒途径中的关键基因，其缺失可长期防止沃勒变性和沃勒样、非损伤诱导的轴突病，这是一种逆行退行性过程，发生在许多轴突运输受损的神经退行性疾病中。在这里，我们通过从 TDP-43、YFP-H 双转基因 ALS-FTD 小鼠模型中删除 Sarm1，探索了 Sarm1 信号是否可以成为 ALS 的治疗靶点。Sarm1 缺失减弱了运动轴突变性和运动神经元终末失神经支配。运动神经元细胞体也得到了显著保护。Sarm1 的缺失也减弱了初级运动皮层中 V 层锥体神经元树突棘的丢失。结构 MRI 确定了内嗅皮层是最明显萎缩的区域，组织学研究证实内嗅皮层神经元的丢失比运动皮层更严重，提示在这种转基因小鼠模型中存在突出的 FTD 样神经退行性变模式。尽管神经元变性减少，但 Sarm1 缺失并不能减轻 TDP-43 引起的与年龄相关的行为缺陷。然而，Sarm1 缺失与 TDP-43 雄性小鼠存活率的显著增加有关，这表明沃勒样通路在 TDP-43 介导的神经退行性变的最早阶段具有有害作用。总的来说，这些结果表明抗 SARM1 策略在 ALS-FTD 中具有治疗潜力。
