Defining mechanisms underlying C9orf72-associated frontotemporal dementia with C. elegans and mammalian models

用线虫和哺乳动物模型定义 C9orf72 相关额颞叶痴呆的机制

• 批准号: 10552038
• 负责人: Robert G Kalb
• 金额: $ 74.57万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552038
• 关键词: Ablation; Alzheimer' s Disease; Antineoplastic Agents; Arginine; BRD2 gene; Biochemical; Biological; Biological Assay; Biological Models; Bromodomain; C9ORF72; CUL3 gene; Caenorhabditis elegans; Cell model; Cells; Cerebral cortex; Cullin Proteins; Degradation Pathway; Dementia; Development; Diagnosis; Dipeptides; Disease; Endometrial Carcinoma; Exhibits; Experimental Models; Frontotemporal Dementia; Gene Expression; Genes; Genetic; Genetic Screening; Genetic Transcription; Glycine; Homologous Gene; Inherited; Introns; Label; Lead; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Missense Mutation; Modeling; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Phenotype; Physical condensation; Proline; Property; Proteins; Proteomics; RNA; Renal carcinoma; Role; System; Temporal Lobe; Testing; Toxic effect; Transcription Regulatory Protein; Translations; Ubiquitination; cancer therapy; druggable target; frontal lobe; frontotemporal lobar dementia amyotrophic lateral sclerosis; gene conservation; induced pluripotent stem cell; inhibitor; insight; knock-down; mutant; neuroprotection; novel; novel therapeutics; nucleocytoplasmic transport; programs; progressive neurodegeneration; protein degradation; small molecule; small molecule inhibitor; stress granule; targeted treatment; transcriptome sequencing; ubiquitin-protein ligase

Frontotemporal dementia (FTD) is the second most common type of inherited dementia following Alzheimer’s disease. FTD is caused by the progressive neurodegeneration of cells in the frontal and temporal lobe of the cerebral cortex. Expansion of a GGGGCC (G4C2) sequence in the first intron of the C9orf72 gene is the most common genetic cause of FTD and is responsible for ~25% of cases. The mechanisms by which expansion of the G4C2 sequence lead to neurodegeneration of specific neurons is incompletely understood. G4C2 RNA is transcribed in both sense and antisense directions and both RNA strands can undergo an unusual type of translation called Repeat Associated non-AG dependent translation (RANT). RANT of the sense and antisense G4C2 RNA produces five distinct dipeptide repeat proteins (DPRs), two of which (PR and GR) confer strong toxicity in multiple model systems. To better understand the pathogenesis of C9orf72-mediated FTD, we generated C. elegans models expressing pure DPRs. Both PR and GR were toxic in worms and caused neurodegeneration. To define genes and pathways causing toxicity, we performed an unbiased genetic suppressor screen and discovered several highly conserved genes that blocked PR50 toxicity. One highly conserved suppressor is the nuclear E3 ligase adaptor SPOP. SPOP is widely studied in cancer since SPOP missense mutations are a major genetic cause of prostate and endometrial cancer. However, SPOP has never been linked to a neurodegenerative disease until now. The role of SPOP in DPR toxicity is conserved, since both SPOP genetic knockdown and an SPOP small molecule inhibitor blocks DPR toxicity in mammalian primary neurons. One major SPOP target in cancer is BRD2/3/4, which are bromodomain-containing transcriptional regulatory proteins. We found that inhibition of the BRD homolog bet-1 suppresses the ability of SPOP mutants to protect against DPR toxicity. Based on these findings, we hypothesize that the SPOP pathway, which is currently being targeted for the treatment of cancer, may also underlie neurodegenerative pathology in C9 disease. To test this hypothesis, we will: 1) determine whether DPRs directly interact with SPOP to modulate known pathological pathways, such as defective nuclear transport and stress granule formation; 2) delineate the mechanism by which SPOP, BRD, and possibly other substrates mediate DPR toxicity; and 3) determine if SPOP is a ‘druggable’ target for neuroprotection against DPRs in mammalian neurons. Our studies will interrogate a novel pathway associated with C9 disease using a diversity of approaches and experimental model systems. The discovery of this novel ubiquitination system could lead to new therapeutic insights for this incurable form of dementia.

额颞叶痴呆（FTD）是继阿尔茨海默病之后第二常见的遗传性痴呆