Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal.
Life and Health Sciences Research Institute/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Mov Disord. 2018 May;33(5):815-826. doi: 10.1002/mds.27292. Epub 2018 Mar 23.
Mitochondrial dysfunction has been implicated in several neurodegenerative diseases. Creatine administration increases concentration of the energy buffer phosphocreatine, exerting protective effects in the brain. We evaluate whether a creatine-enriched diet would be beneficial for a mouse model of spinocerebellar ataxia type 3, a genetically defined neurodegenerative disease for which no treatment is available.
We performed 2 independent preclinical trials using the CMVMJD135 mouse model (treating 2 groups of animals with different disease severity) and wild-type mice, to which 2% creatine was provided for 19 (preclinical trial 1) or 29 (preclinical trial 2) weeks, starting at a presymptomatic age. Motor behavior was evaluated at several time points from 5 to 34 weeks of age, and neuropathological studies were performed at the end of each trial.
Creatine supplementation led to an overall improvement in the motor phenotype of CMVMJD135 mice in both trials, rescuing motor balance and coordination and also restored brain weight, mitigated astrogliosis, and preserved Calbindin-positive cells in the cerebellum. Moreover, a reduction of mutant ataxin-3 aggregates occurred despite maintained steady-state levels of the protein and the absence of autophagy activation. Creatine treatment also restored the expression of the mitochondrial mass marker Porin and reduced the expression of antioxidant enzymes Heme oxygenase 1 (HO1) and NAD(P)H Quinone Dehydrogenase 1 (NQO1), suggesting a beneficial effect at the level of mitochondria and oxidative stress.
Creatine slows disease progression and improves motor dysfunction as well as ameliorates neuropathology of the CMVMJD135 animals, supporting this as a useful strategy to slow the progression of spinocerebellar ataxia type 3. © 2018 International Parkinson and Movement Disorder Society.
线粒体功能障碍与几种神经退行性疾病有关。肌酸的补充增加了能量缓冲磷酸肌酸的浓度，对大脑产生保护作用。我们评估富含肌酸的饮食是否对脊髓小脑共济失调 3 型（一种遗传性神经退行性疾病，目前尚无治疗方法）的小鼠模型有益。
我们使用 CMVMJD135 小鼠模型（对 2 组具有不同疾病严重程度的动物进行治疗）和野生型小鼠进行了 2 项独立的临床前试验，从发病前开始，2%的肌酸喂养 19（临床前试验 1）或 29（临床前试验 2）周。在 5 至 34 周龄的多个时间点评估运动行为，并在每个试验结束时进行神经病理学研究。
肌酸补充在 2 项试验中均改善了 CMVMJD135 小鼠的整体运动表型，改善了运动平衡和协调能力，还恢复了脑重，减轻了星形胶质细胞增生，并保留了小脑的钙结合蛋白阳性细胞。此外，尽管突变型 ataxin-3 聚集体的蛋白表达水平保持稳定，自噬激活不存在，但聚集体的数量减少。肌酸治疗还恢复了线粒体质量标志物 Porin 的表达，并降低了抗氧化酶血红素加氧酶 1（HO1）和 NAD（P）H 醌氧化还原酶 1（NQO1）的表达，提示在线粒体和氧化应激水平有有益作用。
肌酸可减缓疾病进展，改善运动功能障碍，并改善 CMVMJD135 动物的神经病理学，支持这是一种减缓脊髓小脑共济失调 3 型进展的有用策略。
