Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS.
Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS.
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DOI：
10.1073/pnas.2107391119
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发表时间：
2022-03-29
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
我们的研究结果表明，连接蛋白43半通道是肌萎缩性侧索硬化症（ALS）星形细胞介导的运动神经元毒性和疾病传播的通道，是一种共同的机制，可以针对家族性ALS和散发性ALS人群。此外，我们目前的工作提供了托纳伯沙的原理证明，作为一种已经在其他适应症的临床试验中研究过的药物，托纳伯沙可以作为一种潜在的ALS治疗药物。正常情况下，连接蛋白43 （Cx43）缝隙连接和半通道介导中枢神经系统星形胶质细胞间的通讯，并参与肌萎缩侧索硬化（ALS）中星形胶质细胞介导的神经毒性。本研究表明，在ALS小鼠模型中，星形细胞特异性敲除Cx43可减缓疾病在空间和时间上的进展，提供运动神经元（MN）保护，并提高生存率。此外，Cx43在ALS患者死后组织和脑脊液中的表达上调。利用家族性和散发性ALS的人诱导多能干细胞来源的星形胶质细胞（hiPSC-A），我们发现Cx43在星形胶质细胞膜上表达上调，并且Cx43半通道在星形胶质细胞膜上富集。我们还证明，使用GAP 19（一种模拟肽阻断剂）和tonabersat（一种临床测试的小分子）对ALS星形胶质细胞中的cx43 -半通道进行药理学阻断，可提供hiPSC-MN的神经保护，并降低ALS星形胶质细胞介导的神经元高兴奋性。将托那伯沙长期应用于SOD1G93A小鼠，可通过减少反应性星形细胞增生和小胶质细胞增生而产生MN保护作用。综合这些数据，我们的研究确定Cx43半通道是星形胶质细胞介导的疾病进展的通道和疾病修饰性ALS治疗的药理学靶点。
Our results demonstrate that connexin 43 hemichannels are the conduits for amyotrophic lateral sclerosis (ALS) astrocyte-mediated motor neuron toxicity and disease spread, acting as a common mechanism that can target both familial ALS and sporadic ALS populations. Furthermore, our present work provides proof of principle that tonabersat, as a drug already studied in clinical trials for other indications, could serve as a potential ALS therapeutic. Connexin 43 (Cx43) gap junctions and hemichannels mediate astrocyte intercellular communication in the central nervous system under normal conditions and contribute to astrocyte-mediated neurotoxicity in amyotrophic lateral sclerosis (ALS). Here, we show that astrocyte-specific knockout of Cx43 in a mouse model of ALS slows disease progression both spatially and temporally, provides motor neuron (MN) protection, and improves survival. In addition, Cx43 expression is up-regulated in human postmortem tissue and cerebrospinal fluid from ALS patients. Using human induced pluripotent stem cell–derived astrocytes (hiPSC-A) from both familial and sporadic ALS, we establish that Cx43 is up-regulated and that Cx43-hemichannels are enriched at the astrocyte membrane. We also demonstrate that the pharmacological blockade of Cx43-hemichannels in ALS astrocytes using GAP 19, a mimetic peptide blocker, and tonabersat, a clinically tested small molecule, provides neuroprotection of hiPSC-MN and reduces ALS astrocyte-mediated neuronal hyperexcitability. Extending the in vitro application of tonabersat with chronic administration to SOD1G93A mice results in MN protection with a reduction in reactive astrocytosis and microgliosis. Taking these data together, our studies identify Cx43 hemichannels as conduits of astrocyte-mediated disease progression and a pharmacological target for disease-modifying ALS therapies.
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影响因子：
6.2
作者：
Almad AA;Doreswamy A;Gross SK;Richard JP;Huo Y;Haughey N;Maragakis NJ
通讯作者：
Maragakis NJ
影响因子：
9.3
作者：
Cui Y;Masaki K;Yamasaki R;Imamura S;Suzuki SO;Hayashi S;Sato S;Nagara Y;Kawamura MF;Kira J
通讯作者：
Kira J
影响因子：
9.9
作者：
Atassi, Nazem;Berry, James;Leitner, Melanie
通讯作者：
Leitner, Melanie
影响因子：
--
作者：
CHRIST, GJ;MORENO, AP;SPRAY, DC
通讯作者：
SPRAY, DC
影响因子：
2.7
作者：
Chan, WN;Evans, JM;Upton, N
通讯作者：
Upton, N