Department of Medical Genetics, National Taiwan University Hospital, Taipei, 10041, Taiwan.
Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, 10041, Taipei, Taiwan.
Mol Neurobiol. 2018 Jun;55(6):5299-5309. doi: 10.1007/s12035-017-0763-4. Epub 2017 Sep 11.
In Pompe disease, deficient lysosomal acid α-glucosidase (GAA) activity causes glycogen accumulation in the muscles, which leads to weakness, cardiomyopathy, and respiratory failure. Although glycogen accumulation also occurs in the nervous system, the burden of neurological deficits in Pompe disease remains obscure. In this study, a neuron-specific gene therapy was administered to Pompe mice through intracerebroventricular injection of a viral vector carrying a neuron-specific promoter. The results revealed that gene therapy increased GAA activity and decreased glycogen content in the brain and spinal cord but not in the muscles of Pompe mice. Gene therapy only slightly increased the muscle strength of Pompe mice but substantially improved their performance on the rotarod, a test measuring motor coordination. Gene therapy also decreased astrogliosis and increased myelination in the brain and spinal cord of Pompe mice. Therefore, a neuron-specific treatment improved the motor coordination of Pompe mice by lowering glycogen accumulation, decreasing astrogliosis, and increasing myelination. These findings indicate that neurological deficits are responsible for a significant burden in Pompe disease.
在庞贝病中，溶酶体酸性α-葡萄糖苷酶（GAA）活性的缺乏导致肌肉中的糖原积累，从而导致肌肉无力、心肌病和呼吸衰竭。尽管糖原也在神经系统中积累，但庞贝病的神经缺陷负担仍然不清楚。在这项研究中，通过向携带神经元特异性启动子的病毒载体进行脑室内注射，对庞贝病小鼠进行了神经元特异性基因治疗。结果表明，基因治疗增加了 GAA 活性并降低了庞贝病小鼠大脑和脊髓中的糖原含量，但对肌肉没有影响。基因治疗仅略微增加了庞贝病小鼠的肌肉力量，但显著改善了它们在旋转棒上的表现，旋转棒是一种测量运动协调能力的测试。基因治疗还减少了庞贝病小鼠大脑和脊髓中的星形胶质细胞增生并增加了髓鞘形成。因此，神经元特异性治疗通过降低糖原积累、减少星形胶质细胞增生和增加髓鞘形成，改善了庞贝病小鼠的运动协调能力。这些发现表明，神经缺陷是庞贝病的一个重要负担。
