Exploring a new arm of the integrated stress response and its connection to neurodegeneration

Charcot-Marie-Tooth病(CMT)，又称遗传性运动和感觉神经病(HMSN)，是 最常见的遗传性周围神经病，估计患病率为每2500人中有1人， 相当于美国大约12.5万人。CMT专门针对周围神经和 以四肢远端肌肉无力和萎缩为特征，导致进行性运动障碍， 感觉丧失和骨骼畸形。CMT患者尚无根治性治疗方法。最大的基因家族 在CMT中涉及编码氨基酰-tRNA合成酶(AARs)，AARs是催化 蛋白质生物合成中的关键反应，即转移RNA(TRNAs)与其同源氨基酸的荷电 酸。到目前为止，已有5个家系明确了显性AARS突变与CMT之间的因果关系 成员(YARS1、GARS1、AARS1、HARS1和WARs1)。尽管有一些异质性，但临床表现 具有AARSs突变的CMT患者的高度相似，暗示着共同的疾病机制。值得注意的是，我们和 另一些研究表明，cmt引起的突变并不一定影响trna的氨基酰化。 酶的功能。相反，潜在的常见神经毒性功能的获得被认为是原因所在。 然而，对于这种神经病，其分子基础在很大程度上仍然难以捉摸。在这项提案中，我们的目标是测试一个 统一的中心假设，即综合应激反应(ISR)的新臂调控失调，特别是 在核内受AARS调控，参与了CMT的发病机制。我们建议ISR的这个新分支是 与经典的eIF2a磷酸化介导的ISR途径相关但不同。因为不同的 这种应激反应的时间线，我们称之为晚期整合应激反应(LISR)。我们推测 CMT连锁AARs可能都是LISR调节AARs，以及细胞应激反应的失调 CMT系统的突变会导致神经变性。该项目将在密切合作下进行 杨和乔丹诺娃实验室之间的合作，以探索共同的分子机制，显性突变 5种不同的AAR导致CMT。我们的探索将指导未来深入的机制研究和药物 针对这种严重疾病的发展计划。此外，该项目还将增进我们对基本知识的理解 通过建立一条受AARSs特异性调控的新的应激反应途径。

Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy (HMSN), is the most common form of inherited peripheral neuropathy, with an estimated prevalence of 1 in 2500 individuals, equating to approximately 125,000 people in the United States. CMT specifically targets peripheral nerves and is characterized by weakness and wasting of the distal limb muscles leading to progressive motor impairment, sensory loss, and skeletal deformities. No curative therapy is available for CMT patients. The largest gene family implicated in CMT encodes aminoacyl-tRNA synthetases (aaRSs), which are essential enzymes catalyzing a key reaction in protein biosynthesis, namely, the charging of transfer RNAs (tRNAs) with their cognate amino acids. So far, the causality between dominant aaRS mutations and CMT has been firmly established in 5 family members (YARS1, GARS1, AARS1, HARS1, and WARS1). Despite some heterogeneities, clinical presentations of CMT patients with aaRSs mutations are highly similar, implying shared disease mechanisms. Notably, we and others have demonstrated that CMT-causing mutations do not necessarily affect the tRNA aminoacylation function of the enzymes. Instead, a potentially common neurotoxic gain of function is thought to be responsible for the neuropathy, however, its molecular basis remains largely elusive. In this proposal, we aim to test a unifying central hypothesis that dysregulation of a new arm of the Integrated Stress Response (ISR), specifically regulated by aaRSs in the nucleus, contributes to the etiology of CMT. We propose that this new arm of ISR is related to - but distinct from - the classical eIF2a phosphorylation mediated ISR pathway. Because of the different timeline of this stress response, we name it the Late Integrates Stress Response (LISR). We speculate that CMT-linked aaRSs might all be LISR-regulating aaRSs and that dysregulation of the cellular stress response system by CMT mutations results in neurodegeneration. The project will be carried out in close collaboration between Yang and Jordanova labs to explore the shared molecular mechanism by which dominant mutations in 5 different aaRSs cause CMT. Our exploration will direct future in-depth mechanistic studies and drug development programs for this severe disease. Moreover, this project will advance our understanding of basic biology through establishing a new stress response pathway specially regulated by aaRSs.