Elucidating cellular mechanisms underlying neurodegeneration

阐明神经变性的细胞机制

• 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
• 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' 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

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.

巨轴索神经病（GAN）是一种早发的常染色体隐性神经退行性疾病