Elucidating cellular mechanisms underlying neurodegeneration

阐明神经变性的细胞机制

基本信息

批准号：
10647869
负责人：
Puneet Opal
金额：
$ 57.57万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-17 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10647869
关键词：
Adaptor Signaling Protein Adolescent Alzheimer&apos s Disease Amino Acids Antisense Oligonucleotides Autophagocytosis Autophagosome Axon Axonal Transport Behavioral Cell Culture Techniques Cell Nucleus Cell physiology Cells Central Nervous System Clinic Complex Cytoskeleton Data Degradation Pathway Disease Endosomes Environment Event Excision Family Functional disorder Future Genes Goals Impairment Intermediate Filaments Intracellular Transport Knock-out Knockout Mice Light Lysosomes Mediating Mitochondria Modeling Movement Mus Mutate Mutation Names Nerve Degeneration Neurites Neurodegenerative Disorders Neurologic Symptoms Neurons Organelles Parkinson Disease Pathogenesis Pathologic Pathology Pathway interactions Peripheral Nervous System Phenotype Phosphorylation Play Process Proteins Proteomics Quality Control Regulation Reporting Research Role Severities Shapes Signal Pathway Signal Transduction Sirolimus Site Spinal Ganglia Stable Isotope Labeling Swelling Testing Ubiquitin Ubiquitination analog autosome cell type early onset experimental study forgetting giant axonal neuropathy gigaxonin loss of function mutation member multicatalytic endopeptidase complex nervous system disorder neurofilament neuropathology neuroprotection novel protein degradation self assembly small hairpin RNA small molecule therapeutic target therapy development treatment strategy ubiquitin ligase ubiquitin-protein ligase

项目摘要

Giant axonal neuropathy (GAN) is an early-onset, autosomal recessive neurodegenerative disease that impacts the central and peripheral nervous systems. Pathologically, GAN is characterized by the disorganization and aggregation of intermediate filaments (IF). Formed from self-assembling subunits, the IF network spans the cell from the nucleus to the periphery. In GAN, many cell types show abnormalities in the organization of IF, but neurons clearly bear the brunt of the pathology. Axons swell with the accumulation of neuronal IF, and degenerate to cause the neurological symptoms of GAN. The gene mutated in GAN encodes gigaxonin, a protein that belongs to the BTB/Kelch family of E3 ligase-like adaptor proteins. These proteins typically play a role in ubiquitin-proteasome mediated protein degradation. Based on our own data that GAN degrades neuronal IFs, we hypothesize that neurofilament aggregation creates steric roadblocks in neurites that interfere with intracellular transport of organelles such as mitochondria and lysosomes, resulting in downstream pathology. Furthermore, our preliminary data suggest gigaxonin plays a direct role in autophagy via degradation of other substrates. We hypothesize that the disruption of this critical process exacerbates GAN neuropathology by dysregulation of protein and organellar quality control. This proposal comprehensively tests these models; thus the overall goal of our research is to understand the cellular pathogenesis of GAN with a view to inspiring novel treatment strategies.

巨轴突神经病 (GAN) 是一种早发性常染色体隐性遗传神经退行性疾病，影响中枢和周围神经系统。从病理学上来说，GAN 的特点是中间丝（IF）的解体和聚集。 IF 由自组装亚基形成网络横跨细胞从细胞核到外围。在 GAN 中，许多细胞类型表现出异常 IF 的组织，但神经元显然首当其冲。轴突随着积累而膨胀神经元IF，并退化导致GAN的神经症状。 GAN编码中突变的基因 gigaxonin，一种属于 E3 连接酶样接头蛋白 BTB/Kelch 家族的蛋白质。这些蛋白质通常在泛素蛋白酶体介导的蛋白质降解中发挥作用。根据我们自己的数据，GAN 降解神经元 IF，我们假设神经丝聚集在神经突中产生空间障碍干扰线粒体和溶酶体等细胞内运输，导致下游病理学。此外，我们的初步数据表明 gigaxonin 在自噬中发挥直接作用通过其他底物的降解。我们假设这一关键过程的中断会加剧通过蛋白质失调和细胞器质量控制进行 GAN 神经病理学。该提案全面测试这些模型；因此我们研究的总体目标是了解 GAN 的细胞发病机制以期激发新的治疗策略。