BACKGROUND Mutations in the CLN3 gene lead to so far an incurable juvenile-onset neuronal ceroid lipofuscinosis (JNCL) or Batten disease that starts at the age of 4-6 years with a progressive retinopathy leading to blindness. Motor disturbances, epilepsy and dementia manifest during several following years. Most JNCL patients carry the same 1.02-kb deletion in the CLN3 gene, encoding an unusual transmembrane protein, CLN3 or battenin. RESULTS Based on data of genome-wide expression profiling in CLN3 patients with different rate of the disease progression [Mol. Med., 2011, 17: 1253-1261] and our bioinformatic analysis of battenin protein-protein interactions in neurons we propose that CLN3 can function as a molecular chaperone for some plasma membrane proteins, being crucially important for their correct folding in endoplasmic reticulum. Changes in spatial structure of these membrane proteins lead to transactivation of the located nearby receptors. Particularly, CLN3 interacts with a subunit of Na/K ATPase ATP1A1 which changes its conformation and activates the adjacent epidermal growth factor receptor (EGFR). As a result, a large amount of erroneously activated EGFR generates MAPK signal cascades (ERK1/ERK2, JNKs and p38) from cell surface eventually causing neurons' death. CONCLUSIONS Molecular mechanism of the juvenile form of Batten disease (JNCL), which is based on the excessive activation of signaling cascades in a time of the radical increase of neuronal membranes' area in the growing brain, have been proposed and substantiated. The primary cause of this phenomenon is the defective function of the CLN3 protein that could not act properly as molecular chaperone for some plasma membrane proteins in the endoplasmic reticulum. The incorrect three-dimensional structure of at least one such protein, ATP1A1, leads to unregulated spontaneous and repetitive activation of the SRC kinase that transactivates EGFR with the subsequent uncontrolled launch of various MAPK cascades. Possible ways of treatment of patients with JNCL have been suggested. REVIEWERS This article was reviewed by Konstantinos Lefkimmiatis, Eugene Koonin and Vladimir Poroikov.

中文翻译：

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巴滕氏病少年形式的分子机制：MAPK信号通路（ERK1 / ERK2，JNK和p38）在疟疾发病中的重要作用。

背景技术迄今为止，CLN3基因的突变导致无法治愈的少年发作性神经元类脂褐质病（JNCL）或巴顿病，其开始于4-6岁，并伴有进行性视网膜病，导致失明。在接下来的几年中出现了运动障碍，癫痫和痴呆。大多数JNCL患者在CLN3基因中携带相同的1.02-kb缺失，编码一种不同寻常的跨膜蛋白，CLN3或巴丁宁。结果基于具有不同疾病进展率的CLN3患者的全基因组表达谱数据[Mol。Med。，2011，17：1253-1261]和我们对神经元中巴丁宁蛋白-蛋白质相互作用的生物信息学分析，我们建议CLN3可以充当某些质膜蛋白的分子伴侣，对于它们在内质网中的正确折叠至关重要。这些膜蛋白的空间结构变化导致附近受体的反式激活。特别是，CLN3与Na / K ATPase ATP1A1的一个亚基相互作用，从而改变其构象并激活相邻的表皮生长因子受体（EGFR）。结果，大量错误激活的EGFR从细胞表面产生MAPK信号级联反应（ERK1 / ERK2，JNK和p38），最终导致神经元死亡。结论已经提出并证实了巴滕氏病（JNCL）少年形式的分子机制，该机制基于在成长的大脑中神经元膜区域的急剧增加时信号级联反应的过度激活。这种现象的主要原因是CLN3蛋白的功能缺陷，无法正确地充当内质网中某些质膜蛋白的分子伴侣。至少一种这样的蛋白质ATP1A1的错误三维结构会导致SRC激酶的自发性和重复性激活不受控制，而SRC激酶会反过来激活EGFR并随后不受控制地启动各种MAPK级联。已经提出了治疗JNCL患者的可能方法。审阅者本文由Konstantinos Lefkimmiatis，Eugene Koonin和Vladimir Poroikov审阅。导致SRC激酶不受控制的自发性和重复性激活，从而激活EGFR，随后失控地释放各种MAPK级联。已经提出了治疗JNCL患者的可能方法。审阅者本文由Konstantinos Lefkimmiatis，Eugene Koonin和Vladimir Poroikov审阅。导致SRC激酶不受控制的自发性和重复性激活，从而激活EGFR，随后失控地释放各种MAPK级联。已经提出了治疗JNCL患者的可能方法。审阅者本文由Konstantinos Lefkimmiatis，Eugene Koonin和Vladimir Poroikov审阅。