Evidence for aberrant astrocyte hemichannel activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL).
Evidence for aberrant astrocyte hemichannel activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL).
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DOI：
10.1371/journal.pone.0095023
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kielian T
中科院分区：
文献类型：
--
作者：
Burkovetskaya M;Karpuk N;Xiong J;Bosch M;Boska MD;Takeuchi H;Suzumura A;Kielian T
幼年神经性Ceroid Lipofuscinosis （JNCL）是一种溶酶体贮积性疾病，由CLN3常染色体隐性突变引起，可导致视力丧失、进行性认知和运动能力下降以及过早死亡。星形胶质细胞激活的形态学证据发生在疾病过程的早期，并与神经元最终丢失的区域一致。然而，CLN3突变对星形胶质细胞功能的影响仍然相对不明确。星形胶质细胞在中枢神经系统的稳态中发挥着关键作用，部分原因是它们通过形成广泛的合胞网络，通过间隙连接（GJ）通道偶联，调节细胞外环境。相反，非对偶半通道（hc）通过允许分子在细胞内和细胞外环境之间无区别地通过而与中枢神经系统病理有关。在这里，我们检查了CLN3突变小鼠的急性脑切片（CLN3Δex7/8），以确定CLN3缺失是否会改变GJ和HC活性的平衡。与野生型（WT）动物相比，CLN3Δex7/8小鼠在出生后第30天在许多大脑区域显示出星形胶质细胞HC开放的短暂增加；然而，在出生后60天和90天，CLN3Δex7/8星形胶质细胞的HC活性稳步下降，达到低于WT细胞的水平。这表明星形胶质细胞功能的进行性下降，与WT动物相比，CLN3Δex7/8小鼠中谷氨酰胺合成酶、GLAST和连接蛋白表达的显著降低支持了这一点。基于早期星形胶质细胞HC活性的增加，我们用新型卡贝诺洛酮衍生物ni -0602治疗CLN3Δex7/8小鼠以抑制HC。与WT动物相比，给药1个月的INI-0602显著降低了CLN3Δex7/8小鼠大脑中的溶酶体ceroid内含物，这与星形胶质细胞GJ通讯显著增加和星形胶质细胞静息膜电位正常化到WT水平相一致。总的来说，这些发现表明星形胶质细胞通讯的改变可能影响JNCL的进展，并可能提供潜在的治疗靶点。
Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3 that leads to vision loss, progressive cognitive and motor decline, and premature death. Morphological evidence of astrocyte activation occurs early in the disease process and coincides with regions where neuronal loss eventually ensues. However, the consequences of CLN3 mutation on astrocyte function remain relatively ill-defined. Astrocytes play a critical role in CNS homeostasis, in part, by their ability to regulate the extracellular milieu via the formation of extensive syncytial networks coupled by gap junction (GJ) channels. In contrast, unopposed hemichannels (HCs) have been implicated in CNS pathology by allowing the non-discriminant passage of molecules between the intracellular and extracellular milieus. Here we examined acute brain slices from CLN3 mutant mice (CLN3Δex7/8) to determine whether CLN3 loss alters the balance of GJ and HC activity. CLN3Δex7/8 mice displayed transient increases in astrocyte HC opening at postnatal day 30 in numerous brain regions, compared to wild type (WT) animals; however, HC activity steadily decreased at postnatal days 60 and 90 in CLN3Δex7/8 astrocytes to reach levels lower than WT cells. This suggested a progressive decline in astrocyte function, which was supported by significant reductions in glutamine synthetase, GLAST, and connexin expression in CLN3Δex7/8 mice compared to WT animals. Based on the early increase in astrocyte HC activity, CLN3Δex7/8 mice were treated with the novel carbenoxolone derivative INI-0602 to inhibit HCs. Administration of INI-0602 for a one month period significantly reduced lysosomal ceroid inclusions in the brains of CLN3Δex7/8 mice compared to WT animals, which coincided with significant increases in astrocyte GJ communication and normalization of astrocyte resting membrane potential to WT levels. Collectively, these findings suggest that alterations in astrocyte communication may impact the progression of JNCL and could offer a potential therapeutic target.
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影响因子：
2.5
作者：
Corns LF;Deuchars J;Deuchars SA
通讯作者：
Deuchars SA
影响因子：
4.7
作者：
Garg, S;Syed, MM;Kielian, T
通讯作者：
Kielian, T
影响因子：
3.5
作者：
Cotman, SL;Vrbanac, V;MacDonald, ME
通讯作者：
MacDonald, ME
影响因子：
9.9
作者：
Åberg, L;Liewendahl, K;Santavuori, P
通讯作者：
Santavuori, P
DOI：
10.1002/ajmg.1320570250
发表时间：
1995-06-05
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
JOHNSON, DW;SPEIER, S;BOUSTANY, RM
通讯作者：
BOUSTANY, RM