The role of SIRT1 deacetylase in neuromuscular aging and amyotrophic lateral sclerosis

SIRT1 deacetylase functions in a variety of cells and tissues to mitigate age- and disease-induced damages. However, it remains unknown if SIRT1 also acts to prevent pathological changes that accrue in motor units, and specifically alpha-motor neurons, with advancing age and during the progression of amyotrophic lateral sclerosis (ALS). Here, we show that SIRT1 expression decreases in the spinal cord of wild type mice with advancing age. Using mouse models that overexpress or inactivate SIRT1 in motor neurons, we discovered that SIRT1 prevents age-related degeneration of motor neurons' presynaptic sites at neuromuscular junctions (NMJs). We also found that increasing SIRT1 in motor neurons delays degeneration of presynaptic sites at NMJs and extends the lifespan of SOD1G93A mice. Thus, SIRT1 has a similar effect on aging and ALS-affected motor neurons, two conditions in which a remarkable number of transcripts are similarly altered in the spinal cord. These include genes involved in inflammatory and immune responses and genes with known function at synapses. These findings show that SIRT1 functions to mitigate pathological changes induced by aging and ALS, two conditions with a surprising degree of overlap in the spinal cord. Eight replicates spinal cords from mice aged 18-24 months, eight replicates of spinal cords from mice aged 3-4 months, 3 replicates of spinal cords from ALS symptomatic mice aged 5-6 months and 3 replicates of spinal cords from wt controls aged 5-6 months.SIRT1脱乙酰酶（SIRT1 deacetylase）可在多种细胞与组织中发挥功能，以减轻衰老与疾病诱导的损伤。然而目前尚不明确，SIRT1是否同样能够阻止运动单元（尤其是α运动神经元）在衰老进程中以及肌萎缩侧索硬化（amyotrophic lateral sclerosis, ALS）病程进展时逐渐出现的病理变化。本研究证实，野生型小鼠脊髓内的SIRT1表达水平随衰老进程逐步下调。通过构建运动神经元中过表达或失活SIRT1的小鼠模型，我们发现SIRT1可阻断运动神经元在神经肌肉接头（neuromuscular junction, NMJ）处的突触前位点发生衰老相关的退行性改变。我们同时发现，上调运动神经元内的SIRT1表达可延缓神经肌肉接头处突触前位点的退行性病变，并延长SOD1G93A模型小鼠的生存期。由此可见，SIRT1对衰老相关与ALS受累的运动神经元具有相似的保护作用；而在这两种病理状态下，脊髓内存在大量表达模式发生相似改变的转录本，其中包括参与炎症与免疫应答的基因，以及已知在突触中发挥功能的基因。上述研究结果表明，SIRT1可减轻衰老与ALS诱导的病理变化，而这两种病理状态在脊髓中存在出人意料的高度重叠特征。本研究的实验样本包括：18~24月龄小鼠脊髓组织8份生物学重复样本、3~4月龄小鼠脊髓组织8份生物学重复样本、5~6月龄ALS症状期小鼠脊髓组织3份生物学重复样本，以及5~6月龄野生型对照小鼠脊髓组织3份生物学重复样本。