Reversibility of neuropathology in Tay-Sachs-related diseases
Reversibility of neuropathology in Tay-Sachs-related diseases
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DOI：
10.1093/hmg/ddt459
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发表时间：
2014-02-01
影响因子：
3.5
通讯作者：
Cox, Timothy M.
中科院分区：
文献类型：
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作者：
Cachon-Gonzalez, Maria-Begona;Wang, Susan Z.;Cox, Timothy M.
GM2神经节苷脂沉积症是由于溶酶体β -N -乙酰氨基己糖苷酶系统缺陷导致的进行性神经退行性疾病。β -氨基己糖苷酶A和B底物的积累被认为是导致这种致命疾病的原因。一种具有类似于婴儿型GM2神经节苷脂沉积症病理特征的山德霍夫病（SD）的可靠小鼠模型已被描述。我们已经表明，通过向年轻成年SD小鼠颅内递送重组腺相关病毒载体来表达β -氨基己糖苷酶，可以预防该疾病的许多症状并延长寿命。为了研究GM2神经节苷脂沉积症中神经损伤的性质及其可逆性程度，我们研究了SD小鼠疾病的发展过程；我们还探讨了在疾病过程中的关键时间进行基因转移的效果。在此我们报告，只有当治疗基因在疾病明显之前或在其早期表现期间表达时，存活率才会大幅提高。然而，无论何时进行治疗，都观察到β -氨基己糖苷酶广泛且大量表达，从而清除糖缀合物、α -突触核蛋白和泛素化蛋白，并消除炎症反应和神经元丢失。我们还表明，髓鞘形成缺陷在生命早期就会出现，并且当对成年大脑进行治疗时不容易解决。这些结果表明，改善功能和存活率的时间机会有限——但无论GM2神经节苷脂沉积症的主要病理特征是否得到解决，都会达到一个无法阻止功能恶化和死亡的阶段。
The GM2 gangliosidoses are progressive neurodegenerative disorders due to defects in the lysosomal beta-N-acetylhexosaminidase system. Accumulation of beta-hexosaminidases A and B substrates is presumed to cause this fatal condition. An authentic mouse model of Sandhoff disease (SD) with pathological characteristics resembling those noted in infantile GM2 gangliosidosis has been described. We have shown that expression of beta-hexosaminidase by intracranial delivery of recombinant adeno-associated viral vectors to young adult SD mice can prevent many features of the disease and extends lifespan. To investigate the nature of the neurological injury in GM2 gangliosidosis and the extent of its reversibility, we have examined the evolution of disease in the SD mouse; we have moreover explored the effects of gene transfer delivered at key times during the course of the illness. Here we report greatly increased survival only when the therapeutic genes are expressed either before the disease is apparent or during its early manifestations. However, irrespective of when treatment was administered, widespread and abundant expression of beta-hexosaminidase with consequent clearance of glycoconjugates, alpha-synuclein and ubiquitinated proteins, and abrogation of inflammatory responses and neuronal loss was observed. We also show that defects in myelination occur in early life and cannot be easily resolved when treatment is given to the adult brain. These results indicate that there is a limited temporal opportunity in which function and survival can be improved-but regardless of resolution of the cardinal pathological features of GM2 gangliosidosis, a point is reached when functional deterioration and death cannot be prevented.