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肌萎缩侧索硬化(amyotrophic lateral sclerosis,ALS)最显著的病理改变是选择性的运动神经元损害。最近研究表明,运动神经元的缺失主要是由凋亡引起的。变异的过氧化物歧化酶1(superoxide dismutase1,SOD1)通过不确切的机制进入内质网形成蛋白聚集物,和其他不明确的原因一起引起内质网应激(endoplasmic reticulum stress,ERS)和未折叠蛋白反应(unfolded protein response,UPR),进而通过激活Caspase-12、凋亡信号调节激酶(apoptosis-signalregulating kinase1,ASK1)-c-Jun氨基末端激酶(c-Jun-NH2-terminal kinases,JNK)通路、CHOP表达升高、钙离子的释放,引起运动神经元的凋亡。最近研究表明,在罕见的家族性ALS患者的一个亚群中发现了空泡相关膜蛋白相关蛋白B(vesicle-associated membrane protein-associated protein B,VAPB)的显性遗传变异。VAPB在维持内质网稳态中起着一定的作用。变异的VAPB通过加剧ERS、与内质网中脂质代谢所需的酶结合障碍、激活人生红素肝细胞(erythropoietin-producing human hepatocellar,Eph)受体等机制,引起运动神经元的死亡。
The most significant pathological change of amyotrophic lateral sclerosis (ALS) is selective motor neuron damage. Recent studies show that motor neuron loss is mainly caused by apoptosis. Mutant superoxide dismutase 1 (SOD1) enters the endoplasmic reticulum to form protein aggregates by an inaccurate mechanism that, together with other unclear causes, causes endoplasmic reticulum stress (ERS) and Unprotected protein response (UPR), and further activate caspase-12, c-Jun-NH2-terminal kinases (JNK) Pathway, CHOP expression increased, the release of calcium, causing motor neuron apoptosis. Recent studies have shown that a dominant genetic variation of the vacuolar-associated membrane protein-associated protein B (VAPB) was found in a subset of rare familial ALS patients. VAPB plays a role in maintaining the homeostasis of the endoplasmic reticulum. Variant VAPB causes motor neuron death by exacerbating ERS, binding enzymes required for lipid metabolism in the endoplasmic reticulum, and activating mechanisms such as erythropoietin-producing human hepatocellar (Eph) receptors.