Elucidation of mechanism underlying accelerated production of endogenous aldehyde in amyotrophic lateral sclerosis and development of new drug therapy

肌萎缩侧索硬化症(ALS)患者和ALS小鼠模型的脑脊液中有较高水平的4-羟基壬烯醛(HNE)。在本研究中，我们研究了HNE在ALS中的生理作用以及N-乙酰-L半胱氨酸(NAC)及其衍生物NAC-酰胺(NACA)对ALS(G93A)小鼠的保护作用。在G93A的脊髓中，HNE修饰的蛋白质水平在15周(开始运动障碍)和年龄较大时显著增加。在G93A中，给予NAC对疾病进展和生存没有影响。相比之下，服用NACA减缓了这些小鼠的疾病进展和延长了存活时间。这些结果提示，HNE可能参与了G93A区运动神经元的变性，NACA是治疗ALS的有前景的药物。

Higher levels of 4-Hydroxynonenal (HNE) have been shown in the cerebrospinal fluid of amyotrophic lateral sclerosis (ALS) patients and mice models of ALS. In this study, we investigated phathophysiological roles of HNE in ALS and protective potentials of N-acetyl-L-cysteine (NAC) and its derivative, NAC-amide (NACA) in a mouse model of ALS (G93A). The levels of HNE-modified proteins in the spinal cord of the G93A were significantly increased at 15 weeks (onset of motor disturbance) and older. Administration of NAC had no effect on disease progression and survival in the G93A. In contrast, administration of NACA slowed disease progression and prolonged survival in these mice. These results suggest that HNE may play a role in the degeneration of motoneurons in the G93A, and that NACA is a promising therapeutic drug for ALS.