Pore-Forming Proteins as Mediators of Novel Epigenetic Mechanism of Epilepsy.
Pore-Forming Proteins as Mediators of Novel Epigenetic Mechanism of Epilepsy.
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DOI：
10.3389/fneur.2017.00003
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发表时间：
2017
影响因子：
3.4
通讯作者：
Singh V
中科院分区：
文献类型：
--
作者：
Surguchov A;Surgucheva I;Sharma M;Sharma R;Singh V
癫痫是一种大脑疾病，其特征在于具有产生癫痫发作的持久倾向。在过去的二十年中，许多基因缺陷的基础上不同形式的癫痫已被确定与大多数这些基因编码的离子通道蛋白。尽管有这些进展，大多数非家族性癫痫的病因学没有已知的相关基因突变，不能单独用已鉴定的离子通道缺陷来解释。我们假设，从头形成的离子通道的自然未折叠蛋白质（NUPs）增加神经元的兴奋性。改变的离子稳态可能启动/有助于与易感个体癫痫发生相关的细胞级联反应。在这里，我们考虑两个小的蛋白质，即，α-突触核蛋白和stefin B，作为原型的候选人，以说明潜在的机制（S）。先前的工作指出癫痫和α-突触核蛋白或stefin B之间的关联，但这种关联的潜在机制仍然难以捉摸。我们回顾了将这些蛋白质的结构-功能与疾病过程联系起来的证据。可能影响癫痫发生的与DNA序列改变无关的表观遗传机制包括转录或转录后调节。这种表观遗传机制或其组合增强了这些蛋白质的水平，并因此增强了形成环状结构的能力，所述环状结构在掺入膜中后形成新的离子通道并扰乱细胞内离子稳态。替代的表观遗传机制可能通过翻译后修饰改变淀粉样蛋白，从而增加其形成通道的倾向。进一步的研究阐明了通过这些机制形成离子通道的细节及其在癫痫发生中的作用，可能会定义新的分子靶点并指导新药物靶点的开发。
Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. In the last two decades, numerous gene defects underlying different forms of epilepsy have been identified with most of these genes encoding ion channel proteins. Despite these developments, the etiology of majority of non-familial epilepsies has no known associated genetic mutations and cannot be explained by defects in identified ion channels alone. We hypothesize that de novo formation of ion channels by naturally unfolded proteins (NUPs) increases neuronal excitability. Altered ionic homeostasis may initiate/contribute to cellular cascades related to epileptogenesis in susceptible individuals. Here, we consider two small proteins, namely, α-synuclein and stefin B, as prototypical candidates to illustrate the underlying mechanism(s). Previous work points to an association between epilepsy and α-synuclein or stefin B, but the mechanism(s) underlying such association remains elusive. We review the evidence to link the structure–function of these proteins with disease processes. Epigenetic mechanisms unrelated to altered DNA sequence(s) that may affect epileptogenesis include transcriptional or posttranscriptional regulation. Such epigenetic mechanisms or their combination(s) enhance the levels of these proteins and as a result the ability to form annular structures, which upon incorporation into membrane form novel ion channels and disturb intracellular ion homeostasis. Alternative epigenetic mechanisms may change amyloidogenic proteins by posttranslational modifications, thereby increasing their propensity to form channels. Further research elucidating the details about the formation of ion channels through these mechanisms and their role in epileptogenesis may define new molecular targets and guide the development of new drug targets.