A central role for TOR signalling in a yeast model for juvenile CLN3 disease.
A central role for TOR signalling in a yeast model for juvenile CLN3 disease.
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DOI：
10.15698/mic2015.12.241
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发表时间：
2015-11-11
期刊：
影响因子：
--
通讯作者：
Mole SE
中科院分区：
文献类型：
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作者：
Bond ME;Brown R;Rallis C;Bähler J;Mole SE
酵母菌为研究基因在其生物学背景下的功能提供了一个极好的遗传学上易于处理的真核系统，并且与那些引起疾病的保守基因特别相关。我们研究的作用btn1，人类基因的直向同源物的基础上早发性神经退行性疾病（青少年CLN3疾病，神经元蜡样质脂褐质沉积症（NCL）或巴滕病）在裂殖酵母裂殖酵母粟酒裂殖酵母。一个与btn1的遗传相互作用的全球筛选突出了一个保守的关键信号枢纽，其中多个组件在功能上与这个保守的疾病基因相关。这个信号中枢包括两个主要的丝裂原活化蛋白激酶（MAPK）级联，并以Tor激酶复合物TORC 1和TORC 2为中心。我们证实，模拟CLN3疾病的酵母细胞表现出与TORC途径功能障碍一致的特征，并表明调节TORC功能导致该酵母疾病模型中缺陷的全面拯救。相同的途径可能是开发NCL和相关疾病治疗的新靶点。
Yeasts provide an excellent genetically tractable eukaryotic system for investigating the function of genes in their biological context, and are especially relevant for those conserved genes that cause disease. We study the role of btn1, the orthologue of a human gene that underlies an early onset neurodegenerative disease (juvenile CLN3 disease, neuronal ceroid lipofuscinosis (NCLs) or Batten disease) in the fission yeast Schizosaccharomyces pombe. A global screen for genetic interactions with btn1 highlighted a conserved key signalling hub in which multiple components functionally relate to this conserved disease gene. This signalling hub includes two major mitogen-activated protein kinase (MAPK) cascades, and centers on the Tor kinase complexes TORC1 and TORC2. We confirmed that yeast cells modelling CLN3 disease exhibit features consistent with dysfunction in the TORC pathways, and showed that modulating TORC function leads to a comprehensive rescue of defects in this yeast disease model. The same pathways may be novel targets in the development of therapies for the NCLs and related diseases.