mTOR非依赖自噬诱导剂对肌萎缩侧索硬化保护性作用机制的研究

Amyotrophic lateral sclerosis （ALS） is a mortal neurodegenerative disease. Up to now, there is no effective treatment. SOD1 mutation is one of identified etiological factor. Mutant SOD1 mislocalizes in motor neuron and forms aggregates to induce neuronal degeneration and death. Our previous study suggested that mTOR-independent autophagic inducer may have more advantages than mTOR-dependent autophagic inducer in modulating autophagy and treating neurodegenerative disease. Rilmenidine is a drug that can pass blood-brain barrier and treat chronic hypertension in clinical application. Our preliminary show that rilmenidine as a mTOR-independent autophagic inducer can accelerate degeneration of mutant SOD1 and reduce neuronal apoptosis and mitochondrial damage. Moreover, we found that rilmenidine can promote neurite outgrowth in NSC-34 cells for the first time. The present study aims to explore the effect of rilmenidine on neuronal autophagy, ALS progression and neurite outgrowth of motor neurons. We will also study the molecular mechanism of rilmenidine’s protecive effect by means of molecular biological detections, histomorphology observation and behavioral testing. We hope that we can explore a new applicable field for the old drug and provide theoretical basis for clinical ALS treatment.

肌萎缩侧索硬化（amyotrophic lateral sclerosis，ALS）是一种致死性神经变性病，至今尚无有效的治疗方法。SOD1基因突变是ALS鉴定明确的病因，突变的SOD1蛋白质在运动神经元中异常定位、大量聚集，导致运动神经元变性、死亡。我们先前的研究提示mTOR非依赖自噬诱导剂可能对调节神经元自噬、治疗神经变性疾病较mTOR依赖的自噬诱导剂更具优势。利美尼定是临床治疗慢性高血压的药物，同时也是mTOR非依赖的自噬诱导剂，可通过血脑屏障直接作用于中枢神经系统。本课题组初步研究发现利美尼定可促进突变SOD1蛋白质自噬性降解，减少运动神经元凋亡和线粒体损伤。此外，我们首次发现利美尼定可促进运动神经元样细胞神经突起的生长。本项目拟在细胞及动物水平，应用分子生物学检测、组织形态学观察、小鼠行为学检测等方法，探索利美尼定对ALS神经元自噬、ALS病程进展、神经突起生长的作用及分子机制。