Neuroscience Graduate Program.
Department of Molecular Biology, Cellular Biology, and Biochemistry.
JCI Insight. 2023 May 8;8(9):e168448. doi: 10.1172/jci.insight.168448.
Spinal motor neurons have been implicated in the loss of motor function that occurs with advancing age. However, the cellular and molecular mechanisms that impair the function of these neurons during aging remain unknown. Here, we show that motor neurons do not die in old female and male mice, rhesus monkeys, and humans. Instead, these neurons selectively and progressively shed excitatory synaptic inputs throughout the soma and dendritic arbor during aging. Thus, aged motor neurons contain a motor circuitry with a reduced ratio of excitatory to inhibitory synapses that may be responsible for the diminished ability to activate motor neurons to commence movements. An examination of the motor neuron translatome (ribosomal transcripts) in male and female mice reveals genes and molecular pathways with roles in glia-mediated synaptic pruning, inflammation, axonal regeneration, and oxidative stress that are upregulated in aged motor neurons. Some of these genes and pathways are also found altered in motor neurons affected with amyotrophic lateral sclerosis (ALS) and responding to axotomy, demonstrating that aged motor neurons are under significant stress. Our findings show mechanisms altered in aged motor neurons that could serve as therapeutic targets to preserve motor function during aging.
脊髓运动神经元与年龄增长导致的运动功能丧失有关。然而，在衰老过程中损害这些神经元功能的细胞和分子机制仍不清楚。在这里，我们表明，老年雌性和雄性小鼠、恒河猴和人类的运动神经元不会死亡。相反，这些神经元在衰老过程中选择性地、渐进地丧失了整个胞体和树突树突棘上的兴奋性突触输入。因此，衰老的运动神经元包含一个运动回路，其中兴奋性突触与抑制性突触的比例降低，这可能是导致运动神经元激活能力减弱从而开始运动的原因。对雄性和雌性小鼠的运动神经元翻译组（核糖体转录物）的检查显示，在衰老的运动神经元中上调了一些与神经胶质介导的突触修剪、炎症、轴突再生和氧化应激有关的基因和分子途径，这些基因和途径在受影响的运动神经元中也发生了改变，与肌萎缩侧索硬化症（ALS）和对轴突切断的反应。我们的研究结果表明，衰老的运动神经元中存在改变的机制，这些机制可能成为在衰老过程中保持运动功能的治疗靶点。
