Canavan病(CD)是一种隐性遗传性小儿脑白质营养不良,是由少突胶质细胞酶天冬氨酸酰化酶(ASPA)的失活突变引起的。ASPA负责水解氨基酸衍生物N-乙酰基-L-天冬氨酸(NAA),没有它,大脑NAA浓度增加50%或更多。患有CD的婴儿和儿童出现进行性认知和运动延迟,细胞毒性水肿,星形胶质细胞空泡化,和突出的海绵状脑变性。ASPA缺陷型CD小鼠(Aspanur7/nur7)存在类似的NAA升高,广泛的星形胶质细胞功能障碍,共济失调,和浦肯野细胞(PC)树突状萎缩。Bergmannglia(BG),对小脑发育至关重要的放射状星形胶质细胞,与个人电脑紧密交织在一起,它们调节突触的稳定性,功能,和可塑性。BG损伤在许多神经退行性疾病中是常见的,并且经常与PC功能障碍和共济失调有关。这里,我们报告说,在CD小鼠中,BG表现出显著的形态学改变,与PC的结构关联减少,突触支持蛋白的丢失,改变了钙的动力学.我们还发现,在CD小鼠中,BG功能障碍早于小脑液泡化和PC损伤。以前,我们开发了一种针对Nat8l(N-乙酰转移酶-8样,“Nat8lASO”)抑制CD小鼠NAA的产生并逆转共济失调和PC萎缩。这里,我们显示在成年CD小鼠中施用Nat81ASO也导致BG修复。此外,在暴露于NAA升高的星形胶质细胞-神经元共培养物中,阻断星形胶质细胞对NAA的摄取具有神经保护作用。我们的发现表明,BG结构和功能完整性的恢复可能是PC再生和改善运动功能的机制。
Canavan disease (CD) is a recessively inherited pediatric leukodystrophy resulting from inactivating mutations to the oligodendroglial enzyme aspartoacylase (ASPA). ASPA is responsible for hydrolyzing the amino acid derivative N-acetyl-L-aspartate (NAA), and without it, brain NAA concentrations increase by 50% or more. Infants and children with CD present with progressive cognitive and motor delays, cytotoxic edema, astroglial vacuolation, and prominent spongiform brain degeneration. ASPA-deficient CD mice (Aspanur7/nur7 ) present similarly with elevated NAA, widespread astroglial dysfunction, ataxia, and Purkinje cell (PC) dendritic atrophy. Bergmann glia (BG), radial astrocytes essential for cerebellar development, are intimately intertwined with PCs, where they regulate synapse stability, functionality, and plasticity. BG damage is common to many neurodegenerative conditions and frequently associated with PC dysfunction and ataxia. Here, we report that, in CD mice, BG exhibit significant morphological alterations, decreased structural associations with PCs, loss of synaptic support proteins, and altered calcium dynamics. We also find that BG dysfunction predates cerebellar vacuolation and PC damage in CD mice. Previously, we developed an antisense oligonucleotide (ASO) therapy targeting Nat8l (N-acetyltransferase-8-like, \"Nat8l ASO\") that inhibits the production of NAA and reverses ataxia and PC atrophy in CD mice. Here, we show that Nat8l ASO administration in adult CD mice also leads to BG repair. Furthermore, blocking astroglial uptake of NAA is neuroprotective in astroglia-neuron cocultures exposed to elevated NAA. Our findings suggest that restoration of BG structural and functional integrity could be a mechanism for PC regeneration and improved motor function.