Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, USA.
Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
Brain Res. 2018 Jan 15;1679:155-170. doi: 10.1016/j.brainres.2017.11.029. Epub 2017 Dec 5.
In this study, we analyze the neuropathological and biochemical alterations involved in the pathogenesis of a neurodegenerative/movement disorder during different developmental stages in juvenile rats with a mutant Myosin5a (Myo5a). In mutant rats, a spontaneous autosomal recessive mutation characterized by the absence of Myo5a protein expression in the brain is associated with a syndrome of locomotor dysfunction, altered coat color, and neuroendocrine abnormalities. Myo5a encodes a myosin motor protein required for transport and proper distribution of subcellular organelles in somatodendritic processes in neurons. Here we report marked hyperphosphorylation of alpha-synuclein and tau, as well as region-specific buildup of the autotoxic dopamine metabolite, 3,4-dihydroxyphenyl-acetaldehyde (DOPAL), related to decreased aldehyde dehydrogenases activity and neurodegeneration in mutant rats. Alpha-synuclein accumulation in mitochondria of dopaminergic neurons is associated with impaired enzymatic respiratory complex I and IV activity. The behavioral and biochemical lesions progress after 15 days postnatal, and by 30-40 days the animals must be euthanized because of neurological impairment. Based on the obtained results, we propose a pleiotropic pathogenesis that links the Myo5a gene mutation to deficient neuronal development and progressive neurodegeneration. This potential model of a neurodevelopmental disorder with neurodegeneration and motor deficits may provide further insight into molecular motors and their associated proteins responsible for altered neurogenesis and neuronal disease pathogenesis.
在这项研究中，我们分析了神经病理学和生物化学改变在少年大鼠不同发育阶段神经退行性/运动障碍发病机制中的作用，这些大鼠携带有突变型 Myosin5a（Myo5a）。在突变型大鼠中，一种自发的常染色体隐性突变，其特征是大脑中缺乏 Myo5a 蛋白表达，与运动功能障碍、毛色改变和神经内分泌异常的综合征有关。Myo5a 编码一种肌球蛋白马达蛋白，该蛋白在神经元的树突和胞体过程中对细胞器的运输和正确分布是必需的。在这里，我们报告了 alpha-synuclein 和 tau 的明显过度磷酸化，以及特定区域内的自毒性多巴胺代谢物 3,4-二羟基苯乙醛（DOPAL）的积累，这与醛脱氢酶活性降低和突变型大鼠的神经退行性变有关。多巴胺能神经元线粒体中 alpha-synuclein 的积累与酶促呼吸复合物 I 和 IV 活性受损有关。在出生后 15 天，行为和生化损伤会进展，到 30-40 天，由于神经损伤，这些动物必须被安乐死。基于获得的结果，我们提出了一种多效发病机制，将 Myo5a 基因突变与神经元发育不良和进行性神经退行性变联系起来。这种具有神经退行性变和运动缺陷的神经发育障碍的潜在模型可能为改变的神经发生和神经元疾病发病机制的分子马达及其相关蛋白提供进一步的见解。
