Sialidase NEU3 action on GM1 ganglioside is neuroprotective in GM1 gangliosidosis.
Sialidase NEU3 action on GM1 ganglioside is neuroprotective in GM1 gangliosidosis.
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Sialidase NEU3对GM1神经苷的作用在GM1神经节病中具有神经保护作用。
DOI：
10.1016/j.jlr.2023.100463
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发表时间：
2023-12
影响因子：
6.5
通讯作者：
Proia, Richard L.
中科院分区：
文献类型：
--
作者：
Allende, Maria L.;Lee, Y. Terry;Byrnes, Colleen;Li, Cuiling;Tuymetova, Galina;Bakir, Jenna Y.;Nicoli, Elena-Raluca;James, Virginia K.;Brodbelt, Jennifer S.;Tifft, Cynthia J.;Proia, Richard L.
GM 1神经节苷脂沉积症是由编码溶酶体β-半乳糖苷酶的GLB 1基因突变引起的神经退行性疾病。该酶缺乏阻断了GM 1神经节苷脂的催化作用，导致GM 1神经节苷脂和去唾液酸-GM 1神经节苷脂（GA 1糖脂）在脑中积累。这种疾病的严重程度各不相同，残留的β-半乳糖苷酶活性水平主要决定临床病程。完全缺乏β-半乳糖苷酶表达的Glb 1缺失小鼠模型表现出的疾病严重程度低于人类中类似缺陷的预期，表明GM 1神经节苷脂降解途径存在潜在的种属差异。我们假设这种差异可能涉及唾液酸酶NEU 3，它作用于GM 1神经节苷脂产生GA 1糖脂。为了检验这一假设，我们产生了Glb 1/Neu 3双KO（DKO）小鼠。这些小鼠的寿命显著缩短，神经退行性变增加，共济失调比Glb 1 KO小鼠更严重。与Glb 1 KO小鼠相比，Glb 1/Neu 3 DKO小鼠脑显示出GM 1神经节苷脂与GA 1糖脂的比例增加，表明在Glb 1 KO小鼠中，Neu 3介导GM 1神经节苷脂向GA 1糖脂的转化。与Glb 1 KO小鼠相比，Glb 1/Neu 3 DKO小鼠中与神经炎症和胶质反应相关的基因表达增强。小鼠NEU 3比人NEU 3更有效地将GM 1神经节苷脂转化为GA 1糖脂。我们的研究结果强调了NEU 3在改善小鼠Glb 1缺失的后果中的作用，为NEU 3在GM 1神经节苷脂沉积症中小鼠和人类之间的差异效应提供了见解，并为减少GM 1神经节苷脂沉积症患者中毒性GM 1神经节苷脂积累提供了潜在的治疗方法。
GM1 gangliosidosis is a neurodegenerative disorder caused by mutations in the GLB1 gene, which encodes lysosomal β-galactosidase. The enzyme deficiency blocks GM1 ganglioside catabolism, leading to accumulation of GM1 ganglioside and asialo-GM1 ganglioside (GA1 glycolipid) in brain. This disease can present in varying degrees of severity, with the level of residual β-galactosidase activity primarily determining the clinical course. Glb1 null mouse models, which completely lack β-galactosidase expression, exhibit a less severe form of the disease than expected from the comparable deficiency in humans, suggesting a potential species difference in the GM1 ganglioside degradation pathway. We hypothesized this difference may involve the sialidase NEU3, which acts on GM1 ganglioside to produce GA1 glycolipid. To test this hypothesis, we generated Glb1/Neu3 double KO (DKO) mice. These mice had a significantly shorter lifespan, increased neurodegeneration, and more severe ataxia than Glb1 KO mice. Glb1/Neu3 DKO mouse brains exhibited an increased GM1 ganglioside to GA1 glycolipid ratio compared with Glb1 KO mice, indicating that NEU3 mediated GM1 ganglioside to GA1 glycolipid conversion in Glb1 KO mice. The expression of genes associated with neuroinflammation and glial responses were enhanced in Glb1/Neu3 DKO mice compared with Glb1 KO mice. Mouse NEU3 more efficiently converted GM1 ganglioside to GA1 glycolipid than human NEU3 did. Our findings highlight NEU3’s role in ameliorating the consequences of Glb1 deletion in mice, provide insights into NEU3’s differential effects between mice and humans in GM1 gangliosidosis, and offer a potential therapeutic approach for reducing toxic GM1 ganglioside accumulation in GM1 gangliosidosis patients.
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影响因子：
7.4
作者：
Klein DR;Holden DD;Brodbelt JS
通讯作者：
Brodbelt JS
DOI：
10.1096/fj.202101218r
发表时间：
2022-05
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
30.8
作者：
SANGO, K;YAMANAKA, S;PROIA, RL
通讯作者：
PROIA, RL
影响因子：
32.4
作者：
Hammond, Timothy R.;Dufort, Connor;Stevens, Beth
通讯作者：
Stevens, Beth
影响因子：
16
作者：
Sano R;Annunziata I;Patterson A;Moshiach S;Gomero E;Opferman J;Forte M;d'Azzo A
通讯作者：
d'Azzo A