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下降与肌肉质量损失有关 （肌肉减少症）、增加的虚弱以及健康和生活质量的下降。唯一已知的治疗方法 是基于生活方式的，包括锻炼和饮食。啮齿动物模型已被用于证明年龄相关的 神经肌肉接头（NMJ）的变化，包括断裂、重塑和最终的 肌肉去神经支配。正如约书亚·萨尼斯和杰夫·利希特曼雄辩地指出的那样，“成年人的一个关键特征是， NMJ是，它是非常稳定的，在正常情况下，但能够重塑”时，扰动 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受控的， 积极地，但对潜在的分子机制知之甚少”。这是我们最近 推进了领域。在最近发表的一篇论文中，我们证明了稳态可塑性的力量， 保护神经肌肉解剖结构和功能，对生物体健康，行为和 寿命我们称之为“稳态神经保护”。我们建议确定体内平衡是否 神经保护作用抵消了年龄相关的神经肌肉衰退的潜在影响， 老鼠的寿命这将通过在整个寿命期内表征三个独立的小鼠品系来实现。 我们提供了强有力的初步数据支持所有三个基因在进化上保守的作用， 突触前稳态可塑性和小鼠神经肌肉系统加速老化的机制。 年龄是几乎所有神经退行性疾病最重要的风险因素之一。这一系列研究 可能强调了稳态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利影响。

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.