Homeostatic Neuroprotection in the Aging Nervous System

摘要 在人类中，与年龄相关的神经肌肉功能的下降与肌肉质量的丧失有关。 (骨质疏松症)，身体更加虚弱，健康和生活质量下降。唯一已知的治疗方法 是以生活方式为基础的，包括锻炼和节食。啮齿动物模型已经被用来证明与年龄有关的 神经肌肉接头(NMJ)的变化，包括碎裂、重塑和最终 肌肉失神经。正如约书亚·萨内斯和杰夫·利希特曼雄辩地指出的那样，成人的一个关键特征 NMJ是，它在正常情况下非常稳定，但在受到干扰时能够重塑 受伤或年龄。这种稳定性和延展性的结合意味着突触的维持是可控的。 积极，但对潜在的分子机制知之甚少“。这就是我们最近 推进了这一领域。在最近发表的一篇论文中，我们证明了动态平衡可塑性的力量 保护神经肌肉的解剖和功能，对机体的健康、行为和 寿命。我们将其称为“动态平衡神经保护”。我们建议确定动态平衡是否 神经保护可抵消与年龄相关的神经肌肉衰退的潜在影响 小鼠的寿命。这将通过在整个生命周期内对三个独立的老鼠品系进行表征来实现。 我们提供了强有力的初步数据，支持所有三个基因在进化中的保守作用 小鼠神经肌肉系统中突触前稳态可塑性和加速衰老的机制。 年龄是几乎所有神经退行性疾病最重要的风险因素之一。这条研究路线 可能会强调动态平衡神经保护作为未来治疗途径的普遍相关性 改善年龄和神经系统疾病的不良影响。

ABSTRACT In humans, an age-related decline in neuromuscular function is associated with loss of muscle mass (sarcopenia), increased frailty and a degradation of both health and quality of life. The only known treatments are life-style based, including exercise and diet. Rodent models have been used to demonstrate age-related changes at the neuromuscular junction (NMJ) including the fragmentation, remodeling and eventual denervation of muscle. As eloquently stated by Joshua Sanes and Jeff Lichtman, “A key feature of the adult NMJ is that it is remarkably stable under ordinary circumstances yet capable of remodeling” when perturbed by injury or age. “This combination of stability and malleability implies that synaptic maintenance is controlled actively, yet little is known about the underlying molecular mechanisms”. This is where we have recently advanced the field. In a recently published paper we demonstrate the power of homeostatic plasticity to preserve neuromuscular anatomy and function with dramatic effects on organismal health, behavior and lifespan. We refer to this as “Homeostatic Neuroprotection”. We propose to determine whether homeostatic neuroprotection counteracts the insidious effects of age-related neuromuscular decline over the normal lifespan of mice. This will be achieved by characterizing three independent mouse strains across the lifespan. We provide strong preliminary data supporting an evolutionarily conserved role for all three genes in the mechanisms of presynaptic homeostatic plasticity and accelerated aging in the mouse neuromuscular system. Age is one of the most important risk factors for nearly all neurodegenerative disorders. This line of research may underscore the general relevance of homeostatic neuroprotection as a future therapeutic avenue to ameliorate the adverse effects of age and neurological disease.