Evidence for Aberrant Astrocyte Hemichannel Activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL)

被引:41
作者
Burkovetskaya, Maria [1 ,2 ]
Karpuk, Nikolay [1 ,2 ]
Xiong, Juan [1 ,2 ]
Bosch, Megan [3 ,4 ]
Boska, Michael D. [5 ]
Takeuchi, Hideyuki [6 ]
Suzumura, Akio [6 ]
Kielian, Tammy [1 ,2 ]
机构
[1] Univ Nebraska Med Ctr, Dept Pathol, Omaha, NE 68198 USA
[2] Univ Nebraska Med Ctr, Dept Microbiol, Omaha, NE USA
[3] Univ Nebraska Med Ctr, Dept Pharmacol, Omaha, NE USA
[4] Univ Nebraska Med Ctr, Dept Expt Neurosci, Omaha, NE USA
[5] Univ Nebraska Med Ctr, Dept Radiol, Omaha, NE USA
[6] Nagoya Univ, Environm Med Res Inst, Dept Neuroimmunol, Nagoya, Aichi 464, Japan
来源
PLOS ONE | 2014年 / 9卷 / 04期
基金
美国国家卫生研究院;
关键词
JUNCTION INTERCELLULAR COMMUNICATION; MAGNETIC-RESONANCE SPECTROSCOPY; MITOCHONDRIAL ATP SYNTHASE; KNOCK-IN MICE; MOUSE MODEL; BATTEN-DISEASE; GAP-JUNCTIONS; FLUORESCENT DYES; SUBUNIT-C; BRAIN;
D O I
10.1371/journal.pone.0095023
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 (CLN3(Delta ex7/8)) to determine whether CLN3 loss alters the balance of GJ and HC activity. CLN3(Delta ex7/8) 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 CLN3(Delta ex7/8) 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 CLN3(Delta ex7/8) mice compared to WT animals. Based on the early increase in astrocyte HC activity, CLN3(Delta ex7/8) 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 CLN3(Delta ex7/8) 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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页数:18
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