Elucidating cellular mechanisms underlying neurodegeneration

阐明神经变性的细胞机制

基本信息

批准号：
10435954
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/10435954
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 Clinic Complex Data Degradation Pathway Disease 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 Testing Ubiquitin Ubiquitination analog base cell type early onset experimental study giant axonal neuropathy gigaxonin loss of function mutation member multicatalytic endopeptidase complex nervous system disorder neurofilament neuropathology novel protein degradation 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.

巨型轴突神经病（GAN）是一种早期发作的常染色体隐性神经退行性疾病，影响中央和周围神经系统。从病理上讲，甘的特征是中间细丝的混乱和聚集（如果）。由自组装亚基形成网络跨越细胞从细胞核到周围。在GAN中，许多细胞类型在 IF的组织，但神经元显然是病理的首当其冲。轴突随着积累的积累而膨胀神经元IF并退化会引起GAN的神经系统症状。 GAN编码中突变的基因 Gigaxonin，一种属于E3连接酶样衔接蛋白的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起作用。基于我们自己的数据降解神经元IF，我们假设神经丝聚集在神经突中产生空间障碍干扰细胞内细胞器（例如线粒体和溶酶体）的细胞内转运，导致下游病理。此外，我们的初步数据表明，千兆蛋白在自噬中起着直接的作用通过其他底物的降解。我们假设这一关键过程的破坏加剧了蛋白质和细胞器质量控制失调的GAN神经病理学。该建议全面测试这些模型；因此，我们研究的总体目标是了解GAN的细胞发病机理为了鼓舞新的治疗策略。