Striatal neurons expressing full-length mutant huntingtin exhibit decreased N-cadherin and altered neuritogenesis
Striatal neurons expressing full-length mutant huntingtin exhibit decreased N-cadherin and altered neuritogenesis
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DOI：
10.1093/hmg/ddr127
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发表时间：
2011-06-15
影响因子：
3.5
通讯作者：
Seong, Ihn Sik
中科院分区：
文献类型：
--
作者：
Reis, Surya A.;Thompson, Morgan N.;Seong, Ihn Sik
导致亨廷顿病 (HD) 中纹状体细胞脆弱性的扩展 CAG 重复序列编码全长亨廷顿蛋白中的聚谷氨酰胺束，该聚谷氨酰胺束与细胞 [ATP] 和 [ATP/ADP] 相关。由于纹状体神经元容易受到能量不足的影响，我们在 Hdh CAG 敲入小鼠和纹状体细胞中进行了研究，假设能量降低可能会影响神经元 (N)-钙粘蛋白，这是一种候选的能量敏感粘附蛋白，可能有助于 HD 纹状体细胞的敏感性。在体内，N-钙粘蛋白对缺血和全长突变亨廷顿蛋白的影响敏感，随着年龄的增长，Hdh(Q111)纹状体中的N-钙粘蛋白逐渐减少。在培养的纹状体细胞中，N-钙粘蛋白因 ATP 耗竭而减少，而 ST Hdh(Q111) 纹状体细胞由于 Cdh2 mRNA 减少和 N-钙粘蛋白周转增强而表现出 N-钙粘蛋白显着减少，通过补充腺嘌呤以增加 [ATP] 和 [ATP/ADP]，部分正常化。与 N-钙粘蛋白功能下降一致，ST Hdh(Q111) 纹状体细胞在钙依赖性 N-钙粘蛋白介导的细胞聚集和细胞-基质粘附方面表现出严重缺陷，初级 Hdh(Q111) 纹状体神经元细胞表现出 N-钙粘蛋白减少和大量未成熟神经突，其特征是 N-钙粘蛋白和突触小泡标记物的染色呈弥漫性而非聚集性，这部分被腺嘌呤治疗。因此，突变型全长亨廷顿蛋白通过能量缺陷导致纹状体神经元中 N-钙粘蛋白水平降低，对神经突成熟产生不利影响，强烈表明 N-钙粘蛋白介导的信号传导值得在 HD 致病过程的早期进行研究。
The expanded CAG repeat that causes striatal cell vulnerability in Huntington's disease (HD) encodes a polyglutamine tract in full-length huntingtin that is correlated with cellular [ATP] and [ATP/ADP]. Since striatal neurons are vulnerable to energy deficit, we have investigated, in Hdh CAG knock-in mice and striatal cells, the hypothesis that decreased energetics may affect neuronal (N)-cadherin, a candidate energy-sensitive adhesion protein that may contribute to HD striatal cell sensitivity. In vivo, N-cadherin was sensitive to ischemia and to the effects of full-length mutant huntingtin, progressively decreasing in Hdh(Q111) striatum with age. In cultured striatal cells, N-cadherin was decreased by ATP depletion and ST Hdh(Q111) striatal cells exhibited dramatically decreased N-cadherin, due to decreased Cdh2 mRNA and enhanced N-cadherin turnover, which was partially normalized by adenine supplementation to increase [ATP] and [ATP/ADP]. Consistent with decreased N-cadherin function, ST Hdh(Q111) striatal cells displayed profound deficits in calcium-dependent N-cadherin-mediated cell clustering and cell-substratum adhesion, and primary Hdh(Q111) striatal neuronal cells exhibited decreased N-cadherin and an abundance of immature neurites, featuring diffuse, rather than clustered, staining for N-cadherin and synaptic vesicle markers, which was partially rescued by adenine treatment. Thus, mutant full-length huntingtin, via energetic deficit, contributes to decreased N-cadherin levels in striatal neurons, with detrimental effects on neurite maturation, strongly suggesting that N-cadherin-mediated signaling merits investigation early in the HD pathogenic disease process.