Molecular Identity and Location Influence Purkinje Cell Vulnerability in Autosomal-Recessive Spastic Ataxia of Charlevoix-Saguenay Mice.
Molecular Identity and Location Influence Purkinje Cell Vulnerability in Autosomal-Recessive Spastic Ataxia of Charlevoix-Saguenay Mice.
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DOI：
10.3389/fncel.2021.707857
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发表时间：
2021
影响因子：
5.3
通讯作者：
Watt AJ
中科院分区：
文献类型：
--
作者：
Toscano Márquez B;Cook AA;Rice M;Smileski A;Vieira-Lomasney K;Charron F;McKinney RA;Watt AJ
模式化细胞死亡是许多神经退行性疾病的共同特征。在常染色体隐性遗传性痉挛性共济失调的患者和小鼠模型中，已经观察到小脑前蚓部的浦肯野细胞容易变性，而后蚓部的浦肯野细胞具有弹性。已知浦肯野细胞在小脑中以高度定型的模式化方式表达某些分子。其中一种模式化分子是zeolite，它在小脑皮层上以独特的条纹表达。由zeolite和其他模式化分子的表达模式描绘的不同区域与浦肯野细胞死亡的模式有关，这提出了它们是否有助于ARSACS中细胞死亡的问题。我们发现，zebrin图案出现正常的疾病发作之前，在Sacs-/-小鼠，这表明zebrin阳性和阴性浦肯野细胞区正常发展。我们接下来观察到，前小叶III中的zebrin阴性浦肯野细胞优先对细胞死亡敏感，而前zebrin阳性细胞和后zebrin阴性和阳性细胞即使在疾病晚期也保持弹性。小脑核（CN）中的靶神经元的浦肯野细胞神经支配的模式显示出类似的丢失模式：前CN中的神经元，其中输入主要是zebrin阴性的，显示浦肯野细胞神经支配的丢失。与此相反，神经元在后CN，这是由zebrin阴性和阳性斑点，有正常的神经支配。这些结果表明，浦肯野细胞的位置和分子身份决定了它们在ARSACS中对细胞死亡的易感性。
Patterned cell death is a common feature of many neurodegenerative diseases. In patients with autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and mouse models of ARSACS, it has been observed that Purkinje cells in anterior cerebellar vermis are vulnerable to degeneration while those in posterior vermis are resilient. Purkinje cells are known to express certain molecules in a highly stereotyped, patterned manner across the cerebellum. One patterned molecule is zebrin, which is expressed in distinctive stripes across the cerebellar cortex. The different zones delineated by the expression pattern of zebrin and other patterned molecules have been implicated in the patterning of Purkinje cell death, raising the question of whether they contribute to cell death in ARSACS. We found that zebrin patterning appears normal prior to disease onset in Sacs–/– mice, suggesting that zebrin-positive and -negative Purkinje cell zones develop normally. We next observed that zebrin-negative Purkinje cells in anterior lobule III were preferentially susceptible to cell death, while anterior zebrin-positive cells and posterior zebrin-negative and -positive cells remained resilient even at late disease stages. The patterning of Purkinje cell innervation to the target neurons in the cerebellar nuclei (CN) showed a similar pattern of loss: neurons in the anterior CN, where inputs are predominantly zebrin-negative, displayed a loss of Purkinje cell innervation. In contrast, neurons in the posterior CN, which is innervated by both zebrin-negative and -positive puncta, had normal innervation. These results suggest that the location and the molecular identity of Purkinje cells determine their susceptibility to cell death in ARSACS.
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影响因子：
3.5
作者：
Duncan EJ;Larivière R;Bradshaw TY;Longo F;Sgarioto N;Hayes MJ;Romano LEL;Nethisinghe S;Giunti P;Bruntraeger MB;Durham HD;Brais B;Maltecca F;Gentil BJ;Chapple JP
通讯作者：
Chapple JP
影响因子：
3.5
作者：
Perkins EM;Clarkson YL;Suminaite D;Lyndon AR;Tanaka K;Rothstein JD;Skehel PA;Wyllie DJA;Jackson M
通讯作者：
Jackson M
影响因子：
3.5
作者：
Parfitt DA;Michael GJ;Vermeulen EG;Prodromou NV;Webb TR;Gallo JM;Cheetham ME;Nicoll WS;Blatch GL;Chapple JP
通讯作者：
Chapple JP
影响因子：
3.3
作者：
Chung, S. -H.;Marzban, H.;Hawkes, R.
通讯作者：
Hawkes, R.
影响因子：
2.5
作者：
HAWKES, R;LECLERC, N
通讯作者：
LECLERC, N