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Poly(ADP-ribose) promotes the condensation and toxicity of C9orf72 arginine-rich dipeptide repeat proteins

聚（ADP-核糖）促进 C9orf72 富含精氨酸的二肽重复蛋白的缩合和毒性

基本信息

批准号：
10448297
负责人：
Tania France Gendron
金额：
$ 58.25万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10448297
关键词：
Age Arginine Attention Autopsy Behavioral Binding Biological Models Biology C9ORF72 Cell physiology Cells Cerebellum Data Development Diagnosis Dipeptides Disease Disease Pathway Drosophila genus Evaluation Exhibits Eye Functional disorder G3BP1 gene Genes Genetic Gliosis Goals Health Homologous Gene Human In Vitro Investigation Knock-out Light Mediating Molecular Motor Cortex Mus Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Nuclear Pore Complex Proteins Onset of illness Pathogenesis Pathology Patients Phenotype Physical condensation Play Poly Adenosine Diphosphate Ribose Poly(ADP-ribose) Polymerases Pre-Clinical Model Production Proteins Proteomics RNA Ribosomes Role Tissues Toxic effect Transcript Translation Initiation Translations biophysical properties brain tissue c9FTD/ALS effective therapy fly frontal lobe frontotemporal lobar dementia-amyotrophic lateral sclerosis human tissue in vivo knock-down member mouse model neurotoxicity new therapeutic target novel nucleocytoplasmic transport protein TDP-43 protein aggregation sporadic amyotrophic lateral sclerosis stem stress granule therapeutic target therapy development

项目摘要

A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative diseases with no effective treatment. We have shown that transcripts of the expanded repeat undergo an unconventional mode of translation, resulting in the production of five dipeptide repeat proteins (DPRs). Our group and others demonstrated that DPRs form neuronal inclusions throughout the central nervous system of patients with C9orf72-associated ALS and FTD (“c9ALS/FTD”). The identification of this neuropathological hallmark shed new light on possible disease mechanisms, and our systematic assessment of DPRs in human tissues, along with their evaluation in mice and other preclinical models, indicate that the arginine-rich DPRs, poly(GR) and poly(PR), are especially toxic. Our data further suggest that this toxicity stems, at least in part, from the co-condensation and/or co-aggregation of these DPR proteins with proteins that regulate essential cellular functions, such as stress granule biology and nucleocytoplasmic transport. We have also shown that poly(GR) aggregation induces TDP-43 pathology, another hallmark feature of c9ALS/FTD and of the majority of sporadic ALS and FTD cases. Nevertheless, since poly(GR) and poly(PR) interact with more than 200 endogenous proteins, they are likely to adversely influence a host of cellular functions – a line of investigation that merits attention. Also of importance is determining the underlying factors that regulate poly(GR) and poly(PR) condensation and aggregation, and their interactions with other proteins. It is thus notable that our preliminary data show that poly(ADP-ribose) (PAR) promotes poly(GR) and poly(PR) condensation, and enhances their co-condensation or co-aggregation with disease-related proteins in vitro. Moreover, we observed that reducing PAR suppresses poly(GR)- or poly(PR)-mediated neurodegeneration in Drosophila. In light of these exciting findings, we hypothesize that PAR mediates the aggregation and toxicity of arginine-rich DPRs and the proteins to which they bind. Thus, the goal of the proposed project is to determine how PAR does so. To this end, we will identify proteins that interact with poly(GR) or poly(PR) in a PAR-dependent fashion, and investigate the contribution of PAR to arginine-rich DPR aggregation and toxicity using multiple preclinical models and brain tissues from C9orf72 expansion carriers. Overall, by availing the diverse expertise of our team members, we endeavor to elucidate the role of PAR and arginine-rich DPR proteins in c9ALS/FTD pathogenesis, and thus uncover novel therapeutic targets to expedite the development of effective treatments for c9ALS/FTD.

在C9orf72基因中GGGGCC六核苷酸重复扩增是最常见的遗传原因