Hodgkinson Victoria L, Dale Jeffery M, Garcia Michael L, Weisman Gary A, Lee Jaekwon, Gitlin Jonathan D, Petris Michael J
Department of Biochemistry, University of Missouri, Columbia, MO, USA.
Christopher S Bond Life Science Center, University of Missouri, Columbia, MO, USA.
J Pathol. 2015 Jun;236(2):241-50. doi: 10.1002/path.4511. Epub 2015 Mar 3.
ATP7A is a copper-transporting P-type ATPase that is essential for cellular copper homeostasis. Loss-of-function mutations in the ATP7A gene result in Menkes disease, a fatal neurodegenerative disorder resulting in seizures, hypotonia and failure to thrive, due to systemic copper deficiency. Most recently, rare missense mutations in ATP7A that do not impact systemic copper homeostasis have been shown to cause X-linked spinal muscular atrophy type 3 (SMAX3), a distal hereditary motor neuropathy. An understanding of the mechanistic and pathophysiological basis of SMAX3 is currently lacking, in part because the disease-causing mutations have been shown to confer both loss- and gain-of-function properties to ATP7A, and because there is currently no animal model of the disease. In this study, the Atp7a gene was specifically deleted in the motor neurons of mice, resulting in a degenerative phenotype consistent with the clinical features in affected patients with SMAX3, including the progressive deterioration of gait, age-dependent muscle atrophy, denervation of neuromuscular junctions and a loss of motor neuron cell bodies. Taken together, these data reveal autonomous requirements for ATP7A that reveal essential roles for copper in the maintenance and function of the motor neuron, and suggest that SMAX3 is caused by a loss of ATP7A function that specifically impacts the spinal motor neuron.
ATP7A是一种铜转运P型ATP酶，对细胞铜稳态至关重要。ATP7A基因的功能丧失突变会导致门克斯病，这是一种致命的神经退行性疾病，由于全身铜缺乏，会导致癫痫发作、肌张力减退和发育不良。最近研究表明，ATP7A中不影响全身铜稳态的罕见错义突变会导致X连锁3型脊髓性肌萎缩症（SMAX3），这是一种远端遗传性运动神经病。目前尚缺乏对SMAX3的机制和病理生理基础的了解，部分原因是已证明致病突变赋予ATP7A功能丧失和功能获得特性，且目前尚无该疾病的动物模型。在本研究中，Atp7a基因在小鼠运动神经元中被特异性敲除，导致出现与SMAX3受影响患者临床特征一致的退行性表型，包括步态逐渐恶化、年龄依赖性肌肉萎缩、神经肌肉接头失神经支配以及运动神经元细胞体丧失。综上所述，这些数据揭示了对ATP7A的自主需求，表明铜在运动神经元的维持和功能中起重要作用，并提示SMAX3是由ATP7A功能丧失引起的，该功能丧失特异性影响脊髓运动神经元。
