Ablation of keratan sulfate accelerates early phase pathogenesis of ALS.
Ablation of keratan sulfate accelerates early phase pathogenesis of ALS.
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DOI：
10.1371/journal.pone.0066969
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kadomatsu K
中科院分区：
文献类型：
--
作者：
Hirano K;Ohgomori T;Kobayashi K;Tanaka F;Matsumoto T;Natori T;Matsuyama Y;Uchimura K;Sakamoto K;Takeuchi H;Hirakawa A;Suzumura A;Sobue G;Ishiguro N;Imagama S;Kadomatsu K
生物聚合物由三大类组成，即，多核苷酸（DNA、RNA）、多肽（蛋白质）和多糖（糖链）。多核苷酸和多肽在神经退行性疾病的发病机制中起着重要作用。但是，糖链在这一过程中的研究很少，它们的生物学/临床意义在很大程度上仍未被探索。肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种运动神经元退行性疾病，其发病机制需要细胞自主和非细胞自主两种机制。在这里，我们研究了硫酸角质素（KS），硫酸化的蛋白多糖的长糖链，在ALS发病机制中的作用。我们采用ALS模型SOD 1G 93 A小鼠和GlcNAc 6ST-1−/−小鼠，它们在中枢神经系统中缺乏KS。出乎意料的是，SOD 1G 93 AGlcNAc 6ST-1−/−小鼠表现出比SOD 1G 93 A小鼠明显更短的寿命和加速出现临床症状（体重减轻和旋转杆性能下降）。KS表达诱导专门在SOD 1G 93 A小鼠的小胶质细胞亚群，并成为可检测到周围的运动神经元在前角在早期疾病阶段体重减轻之前。在此阶段，M2小胶质细胞标记物的表达在SOD 1G 93 A小鼠中短暂增强，而这种增强在SOD 1G 93 AGlcNAc 6ST-1−/−小鼠中减弱。与此一致，在SOD 1G 93 AGlcNAc 6ST-1−/−小鼠的早期疾病阶段，M2小胶质细胞明显较少。此外，在一些人类ALS病例中也检测到小胶质细胞中KS表达。这项研究表明KS在ALS的早期发病机制中发挥着不可或缺的抑制作用，并可能代表治疗干预的新靶点。
Biopolymers consist of three major classes, i.e., polynucleotides (DNA, RNA), polypeptides (proteins) and polysaccharides (sugar chains). It is widely accepted that polynucleotides and polypeptides play fundamental roles in the pathogenesis of neurodegenerative diseases. But, sugar chains have been poorly studied in this process, and their biological/clinical significance remains largely unexplored. Amyotrophic lateral sclerosis (ALS) is a motoneuron-degenerative disease, the pathogenesis of which requires both cell autonomous and non-cell autonomous processes. Here, we investigated the role of keratan sulfate (KS), a sulfated long sugar chain of proteoglycan, in ALS pathogenesis. We employed ALS model SOD1G93A mice and GlcNAc6ST-1−/− mice, which are KS-deficient in the central nervous system. Unexpectedly, SOD1G93AGlcNAc6ST-1−/− mice exhibited a significantly shorter lifespan than SOD1G93A mice and an accelerated appearance of clinical symptoms (body weight loss and decreased rotarod performance). KS expression was induced exclusively in a subpopulation of microglia in SOD1G93A mice, and became detectable around motoneurons in the ventral horn during the early disease phase before body weight loss. During this phase, the expression of M2 microglia markers was transiently enhanced in SOD1G93A mice, while this enhancement was attenuated in SOD1G93AGlcNAc6ST-1−/− mice. Consistent with this, M2 microglia were markedly less during the early disease phase in SOD1G93AGlcNAc6ST-1−/− mice. Moreover, KS expression in microglia was also detected in some human ALS cases. This study suggests that KS plays an indispensable, suppressive role in the early phase pathogenesis of ALS and may represent a new target for therapeutic intervention.
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影响因子：
3.7
作者：
Takeuchi H;Mizoguchi H;Doi Y;Jin S;Noda M;Liang J;Li H;Zhou Y;Mori R;Yasuoka S;Li E;Parajuli B;Kawanokuchi J;Sonobe Y;Sato J;Yamanaka K;Sobue G;Mizuno T;Suzumura A
通讯作者：
Suzumura A
表达ALS连接突变体SOD1的原代星形胶质细胞的转录谱。
影响因子：
4.2
作者：
Vargas, Marcelo R.;Pehar, Mariana;Diaz-Amarilla, Pablo J.;Beckman, Joseph S.;Barbeito, Luis
通讯作者：
Barbeito, Luis
影响因子：
5.3
作者：
Liao, Bing;Zhao, Weihua;Beers, David R.;Henkel, Jenny S.;Appel, Stanley H.
通讯作者：
Appel, Stanley H.
影响因子：
5.3
作者：
Ponomarev, Eugene D.;Maresz, Katarzyna;Dittel, Bonnie N.
通讯作者：
Dittel, Bonnie N.
DOI：
10.1523/jneurosci.3257-09.2009
发表时间：
2009-10-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kigerl KA;Gensel JC;Ankeny DP;Alexander JK;Donnelly DJ;Popovich PG
通讯作者：
Popovich PG