Department of Medicine, University of Cambridge, Level 5 Addenbrooke's Hospital, Box 157, Hills Road, Cambridge CB2 0QQ, UK.
Hum Mol Genet. 2011 Nov 15;20(22):4371-80. doi: 10.1093/hmg/ddr364. Epub 2011 Aug 18.
Sandhoff disease, a GM2 gangliosidosis caused by a deficiency in β-hexosaminidase, is characterized by progressive neurodegeneration. Although loss of neurons in association with lysosomal storage of glycosphingolipids occurs in patients with this disease, the molecular pathways that lead to the accompanying neurological defects are unclear. Using an authentic murine model of GM2 gangliosidosis, we examined the pattern of neuronal loss in the central nervous system and investigated the effects of gene transfer using recombinant adeno-associated viral vectors expressing β-hexosaminidase subunits (rAAV2/1-Hex). In 4-month-old Sandhoff mice with neurological deficits, cells staining positively for the apoptotic signature in the TUNEL reaction were found in the ventroposterior medial and ventroposterior lateral (VPM/VPL) nuclei of the thalamus. There was progressive loss of neuronal density in this region with age. Comparable loss of neuronal density was identified in the lateral vestibular nucleus of the brainstem and a small but statistically significant loss was present in the ventral spinal cord. Loss of neurons was not detected in other regions that were analysed. Administration of rAAV2/1-Hex into the brain of Sandhoff mice prevented the decline in neuronal density in the VPM/VPL. Preservation of neurons in the VPM/VPL was variable at the humane endpoint in treated animals, but correlated directly with increased lifespan. Loss of neurons was localized to only a few regions in the Sandhoff brain and was prevented by rAAV-mediated transfer of β-hexosaminidase gene function at considerable distances from the site of vector administration.
沙夫病（Sandhoff disease）是一种由β-己糖胺酶缺乏引起的 GM2 神经节苷脂贮积症，其特征是进行性神经退行性变。虽然这种疾病患者的神经元丧失与溶酶体糖脂储存有关，但导致伴随神经缺陷的分子途径尚不清楚。我们使用 GM2 神经节苷脂贮积症的真实鼠模型，研究了中枢神经系统中神经元丧失的模式，并研究了使用表达β-己糖胺酶亚基的重组腺相关病毒载体（rAAV2/1-Hex）进行基因转移的效果。在有神经功能缺损的 4 月龄沙夫病鼠中，在丘脑的腹后内侧核和腹后外侧核（VPM/VPL）中发现了 TUNEL 反应呈阳性的凋亡标记细胞。随着年龄的增长，该区域的神经元密度逐渐丧失。在脑干外侧前庭核中也发现了类似的神经元密度丧失，并且在脊髓腹侧也存在统计学上显著的小量丧失。在分析的其他区域未发现神经元丧失。将 rAAV2/1-Hex 注入沙夫病鼠的脑内可防止 VPM/VPL 中神经元密度的下降。在治疗动物的人道终点时，VPM/VPL 中神经元的保存情况是可变的，但与寿命延长直接相关。在沙夫病鼠的大脑中，神经元丧失仅局限于少数几个区域，并且 rAAV 介导的β-己糖胺酶基因功能转移可在距载体给药部位相当远的距离处预防神经元丧失。
