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Identifying the molecular mechanisms of GEMIN5 mutations in a novel cerebellar ataxia syndrome

鉴定新型小脑共济失调综合征中 GEMIN5 突变的分子机制

基本信息

批准号：
10753403
负责人：
Udai B Pandey
金额：
$ 53.97万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753403
关键词：
Affect Age of Onset Alternative Splicing Animals Applications Grants Ataxia Atrophic Behavior Biochemical Biogenesis Biological Biological Assay Biological Models Brain CRISPR/Cas technology Cells Cerebellar Ataxia Clinical Coenzyme Q10 Complex DNA Defect Developmental Delay Disorders Disease Drosophila genus Family Fibroblasts Foundations GEMIN5 gene Genetic Guide RNA Heterozygote Homologous Gene Human In Vitro Individual Induced pluripotent stem cell derived neurons Infant Intervention Lead Light Longevity Mitochondria Modeling Molecular Morphology Motor Motor Neuron Disease Motor Neurons Mus Mutation Neurologic Neurons Pathogenesis Pathogenicity Pathway interactions Patients Physiological Process Proteins Proteomics RNA Splicing RNA-Binding Proteins Reporting Respiration Rigor Mortis Role SMN protein (spinal muscular atrophy)SMN1 gene Small Nuclear Ribonucleoproteins Spinal Muscular Atrophy Spliceosomes Symptoms Syndrome Testing Time Transcript Transgenic Mice Transgenic Model Translations Variant autosome clinically relevant disease-causing mutation fly genetic variant human disease in vivo knock-down loss of function mRNA Precursor mitochondrial dysfunction motor disorder motor neuron degeneration mouse model mutant novel pharmacologic polysome profiling premature protein complex protein expression protein function protein protein interaction snRNP Structural Core Protein transcriptome sequencing translatome

项目摘要

Abstract GEMIN5, an RNA-binding protein, is essential for assembly of the Survival Motor Neuron (SMN) complex. GEMIN5 facilitates the formation of small nuclear ribonucleoproteins (snRNPs; the building blocks of spliceosomes). We identified novel autosomal recessive variants in the GEMIN5 gene in multiple patients presenting with motor dysfunction, ataxia, and cerebellar atrophy. Our proposed studies are aimed to understand the molecular mechanisms of mutant GEMIN5 responsible for causing the neurological abnormalities in our patients. We found that patient a significant decrease in GEMIN5 protein levels and reduced protein stability in patient iPSC neurons suggesting a possible loss of function mechanism. Our in vitro assembly assay showed that GEMIN5 variants perturb snRNP assembly formation. To understand the consequences of loss of function GEMIN5, we knockdown endogenous rigor mortis, the Drosophila homologue of human GEMIN5, in Drosophila. Knockdown of rigor mortis (rig) caused motor dysfunction, reduced life span and developmental delay. Interestingly, we observed that CoQ10 levels were significantly reduced in human patient cells and our drosophila model. Treatment with CoQ10 reduced the disease course in human GEMIN5 patients. We generated a mouse model of Gemin5 using CRISPR/cas9 and found early lethality in mice. Our proposed studies are aimed to understand the molecular mechanisms of GEMIN5 by 1) conducting functional analysis of mutant GEMIN5 patient neurons; 2) examining if GEMIN5 variants cause mitochondrial dysfunctions in vivo and iPSC neurons; and 3) investigating the mechanisms of GEMIN5 mutations in mouse models. We expect to identify the molecular pathways that are perturbed in human patients.

摘要