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

探索综合应激反应的新分支及其与神经退行性变的联系

• 批准号: 10303995
• 负责人: Xiang-Lei Yang
• 金额: $ 41.06万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303995
• 关键词: Affect; Amino Acids; Amino Acyl-tRNA Synthetases; Aminoacylation; Architecture; Biology; Cell Nucleus; Cell Survival; Cells; Cellular Stress Response; Characteristics; Charcot-Marie-Tooth Disease; Clinical; Collaborations; Cytoplasm; Deformity; Disease; Distal; Drosophila genus; Enzymes; Etiology; Eukaryotic Cell; Eukaryotic Initiation Factors; Event; Family member; Future; Gene Family; Genes; Genetic; Grant; Hereditary Motor and Sensory Neuropathies; Heterogeneity; Individual; Inherited; Limb structure; Link; Mammalian Cell; Mediating; Metabolic stress; Modeling; Molecular; Molecular Profiling; Muscle; Mutation; Names; Nerve Degeneration; Neurodegenerative Disorders; Neuropathy; Nuclear; Nuclear Translocation; Pathogenesis; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System Diseases; Phosphorylation; Prevalence; Program Development; Property; Protein Biosynthesis; Reaction; Recovery; Role; Sensory; Signal Transduction; Stress; Symptoms; System; Testing; Therapeutic; Time; TimeLine; Transcriptional Activation; Transfer RNA Aminoacylation; Translations; United States; Yang; activating transcription factor; arm; biological adaptation to stress; curative treatments; disease-causing mutation; disorder subtype; drug development; environmental stressor; fly; gain of function; gene repression; in vivo; in vivo Model; in vivo evaluation; insight; motor impairment; neurotoxic; repaired; skeletal; therapeutic development; treatment strategy; upstream kinase; wasting

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.

charcot-marie-tooth病（CMT），也称为遗传性运动和感觉神经病（HMSN）是 遗传性周围神经病的最常见形式，估计患病率为2500人，有1个， 在美国约有大约125,000人。 CMT专门针对周围神经和 其特征是无力和浪费远端的肢体肌肉导致渐进运动障碍， 感觉丧失和骨骼畸形。 CMT患者没有治疗疗法。最大的基因家族 与CMT相关的编码氨基酰基-TRNA合成酶（AARSS），这是催化A的必不可少的酶 蛋白质生物合成中的关键反应，即转移RNA（TRNA）与同源氨基的充电 酸。到目前为止，在5个家庭中牢固地建立了主要的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 AARSS突变的CMT患者高度相似，这意味着共同的疾病机制。值得注意的是，我们和 其他人已经证明，引起CMT的突变不一定会影响tRNA氨基酰化 酶的功能。取而代 然而，对于神经病而言，其分子依据仍然难以捉摸。在此提案中，我们旨在测试 统一中心假设，即综合应力响应的新组（ISR）的失调，特别是 由核中的AARS调控，有助于CMT的病因。我们建议ISR的新部门是 与 - 但与 - 经典的EIF2A磷酸化介导的ISR途径有关。因为不同 这种压力响应的时间表，我们将其命名为晚期压力反应（LISR）。我们推测 CMT连接的AARS可能都在调节AARS，并且细胞应力反应失调 CMT突变系统导致神经退行性。该项目将在密切合作中进行 在杨和约旦诺娃实验室之间探索共同的分子机制，通过这些机制，占主导地位的突变 5种不同的AARS引起CMT。我们的探索将指导未来的深入机械研究和药物 这种严重疾病的发展计划。此外，该项目将提高我们对基本的理解 通过建立专门由AARS调节的新的压力反应途径生物学。

项目成果

An Adapted GeneSwitch Toolkit for Comparable Cellular and Animal Models: A Proof of Concept in Modeling Charcot-Marie-Tooth Neuropathy.

• DOI: 10.3390/ijms242216138
• 发表时间: 2023-11-09
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling.

• DOI: 10.1038/s41467-023-35908-3
• 发表时间: 2023-03-08
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Ermanoska, Biljana;Asselbergh, Bob;Morant, Laura;Petrovic-Erfurth, Maria-Luise;Hosseinibarkooie, Seyyedmohsen;Leitao-Goncalves, Ricardo;Almeida-Souza, Leonardo;Bervoets, Sven;Sun, Litao;Lee, LaTasha;Atkinson, Derek;Khanghahi, Akram;Tournev, Ivaylo;Callaerts, Patrick;Verstreken, Patrik;Yang, Xiang-Lei;Wirth, Brunhilde;Rodal, Avital A.;Timmerman, Vincent;Goode, Bruce L.;Godenschwege, Tanja A.;Jordanova, Albena
• 通讯作者: Jordanova, Albena