Development of a mouse model of C9ORF72 ALS/FTD expressing RAN translated peptide

表达 RAN 翻译肽的 C9ORF72 ALS/FTD 小鼠模型的开发

基本信息

批准号：
8930217
负责人：
Davide Trotti
金额：
$ 19.5万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8930217
关键词：
Accounting Address Affect Amyotrophic Lateral Sclerosis Arginine C9ORF72 Cell Culture Techniques Cell Death Cell Nucleolus Cell model Cells Clinical Dementia Development Dipeptides Disease Drosophila eye Drosophila genus Exhibits Eye Frontotemporal Dementia G-Quartets Genes Genetic Goals Health Human Image In Vitro Individual Introns Investigation Knowledge Lead Length Life Link Modeling Motor Motor Neurons Mus Nerve Degeneration Neuraxis Neurons Nuclear Nucleotides Pathology Patients Peptides Phenotype Population Process Proline Proteins RNA Reporting Research Role Severity of illness Spinal Cord Stress Symptoms Testing Therapeutic Therapeutic Intervention Time Toxic effect Transcript Transgenic Mice Transgenic Organisms Translating Translations Untranslated RNA base cellular imaging frontal lobe in vivo mouse model neurotoxic neurotoxicity nucleolin prevent tool

项目摘要

DESCRIPTION (provided by applicant): Research on ALS has recently been the subject of major advances. Two independent groups have identified an expansion of GGGGCC repeats in the non-coding region of the first intron of the C9ORF72 gene as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and FTD (frontotemporal dementia) identified to date. Accumulation of RNA transcripts containing GGGGCC (sense) or CCCCGG (antisense) repeats were found to aggregate in nuclear foci in frontal cortex and spinal cord in C9ORF72 ALS/FTLD patients. Recently, toxicity of dipeptide repeat products (DPRs) generated via repeat associated non-ATG (RAN) translation of GGGGCC or CCCCGG repeat expansions has been proposed as potential pathogenic mechanism in C9- ALS/FTD, and DPR aggregates have been detected in affected and non-affected regions in ALS and ALS/FTD patients. RAN translation from sense and anti-sense directions has been reported in several nucleotide repeat disorders, including C9-ALS/FTD, making RAN translation an established occurrence in these expansion disorders, and also implicating a pathogenic role for RAN translated proteins. We established cellular models of C9-ALS/FTD using primary motor and cortical neurons, which are known to degenerate in ALS/FTD. By expressing fluorescently tagged homopolymeric C9RAN proteins (or DPRs) we were able to decipher their respective impact on neuronal viability using longitudinal time-lapse live-cell imaging, transgenic Drosophila models and found that Proline-Arginine dipeptides (PR) are robustly neurotoxic when expressed in vitro and in vivo. As next step in our investigation, we propose here to generate transgenic mice that express PR dipeptide repeats. Our hypothesis is that expression of PR aggregates in disease-relevant neuronal populations in mice will result in development of key phenotypes and pathologies that resemble those in ALS/FTD patients. This hypothesis is formulated based on extensive evidence of gained toxicity of PR aggregates in neuronal cell culture models as well as eye degeneration and lethality phenotypes when PR proteins are expressed in Drosophila eye and motor neurons. The rationale of the proposed research is that, once the model is fully characterized, it will have the potential to become a vital tool to unravel the basic mechanisms behind neurodegenerative processes in C9-ALS/FTD and, ultimately, for development of therapeutic interventions.

描述（由申请人提供）：对ALS的研究最近是主要进步的主题。迄今为止，发现CCCGG（反义）重复的FTD（额颞痴呆），最近在额叶皮层中汇总了C9ORF72 ALS/FTLD患者的脊髓，并通过重复相关的非ATG（RAN）翻译而来在ALS和ALS/FTD患者中，C9-ALS/FTD中的潜在致病机制被抗性。蛋白质。我们使用原代摩托子神经建立了C9-als/ftd的Cellaru模型，该模型已在ALS/FTD中退化。 - 在体外表达和体内，我们提出的转基因小鼠表达了PR-PR二肽的重复小鼠将基于神经元培养模型的毒性以及当PR蛋白在果蝇和运动神经元中表达PR蛋白时的毒性以及眼睛的变性和致死性拟议的研究是，一旦模型充分表征，它将有可能成为C9-ALS/FTD a中神经肾脏过程背后的基本机制的重要性。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pathogenic determinants and mechanisms of ALS/FTD linked to hexanucleotide repeat expansions in the C9orf72 gene.

DOI：
10.1016/j.neulet.2016.09.007
发表时间：
2017-01-01
期刊：
Neuroscience letters
影响因子：
2.5
作者：
Wen X;Westergard T;Pasinelli P;Trotti D
通讯作者：
Trotti D

JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer's disease.

DOI：
10.1038/s41467-023-43728-8
发表时间：
2023-12-04
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Scopa, Chiara;Barnada, Samantha M.;Cicardi, Maria E.;Singer, Mo;Trotti, Davide;Trizzino, Marco
通讯作者：
Trizzino, Marco

Repeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation and stress.

C9orf72-ALS/FTD 中重复相关的非 AUG 翻译是由神经元兴奋和应激驱动的。

DOI：
10.15252/emmm.201809423
发表时间：
2019
期刊：
EMBO molecular medicine
影响因子：
11.1
作者：
Westergard,Thomas;McAvoy,Kevin;Russell,Katelyn;Wen,Xinmei;Pang,Yu;Morris,Brandie;Pasinelli,Piera;Trotti,Davide;Haeusler,Aaron
通讯作者：
Haeusler,Aaron