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Mechanisms of SPG4 Hereditary Spastic Paraplegia

SPG4遗传性痉挛性截瘫的机制

基本信息

批准号：
10267690
负责人：
PETER W. BAAS
金额：
$ 64.1万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10267690
关键词：
Accounting Address Adult Alleles Animals Applications Grants Autophagocytosis Axon Back Behavioral Brain Cell physiology Code Communities Corticospinal Tracts Coupled Data Defect Development Disease Down-Regulation Enzymes Etiology Experimental Models Genes Genetic Hereditary Spastic Paraplegia Heritability Human Individual Knowledge Limb structure Link Lower Extremity Mediating Membrane Microtubules Modeling Molecular Motors Motor Neurons Movement Mus Mutation Neurodegenerative Disorders Neurons Organelles Pathogenesis Pathogenicity Pathologic Patients Pattern Phenotype Principal Investigator Property Protein Isoforms Proteins Reporter Reporting Spastic Gait Spinal Cord Swelling Symptoms Techniques Testing Toxic effect Transgenic Mice Transgenic Organisms Translations UCHL1 gene Work autosomal dominant mutation axonal degeneration base casein kinase II cytotoxic effective therapy fast axonal transport gain of function in vivo innovation loss of function motor neuron degeneration mouse model mutant negative affect nervous system disorder novel prevent selective expression spasticity spastin tool

项目摘要

PROJECT SUMMARY / ABSTRACT Hereditary Spastic Paraplegias (HSP) are heritable neurodegenerative diseases in which progressive degeneration of corticospinal axonal tracts results in limb weakness, spasticity and gait deficiencies. These symptoms result from a dying back pattern of degeneration of corticospinal axons, which also display prominent swellings of unclear pathological significance. The commonest form of HSP, termed SPG4-HSP, is caused by mutations in the SPAST gene, which codes for a microtubule-severing protein called spastin. To date, the prevailing mechanistic hypothesis for the etiology of SPG4-HSP is haploinsufficiency, meaning that the corticospinal tracts degenerate because of insufficient functional spastin. However, several major disease features are not readily explained by this etiology, and it is not clear how reduced microtubule severing would promote corticospinal axonal degeneration. Providing novel information that may fill a major gap in our knowledge of SPG4-HSP pathogenesis, recent work of the Principal Investigators revealed toxic properties of mutant spastin proteins, suggesting that a gain-of-function mechanism operates in SPG4-HSP. Curiously, both mechanisms negatively affect fast axonal transport (FAT), a cellular process fueled by molecular motor proteins that allows bidirectional movement of vesicular cargoes along axons. Based on a strong experimental premise, it is hypothesized in this multi-PI grant proposal that abnormalities in microtubule organization associated with reduced spastin levels cause FAT deficits and axonal swellings (loss-of-function). On the other hand, toxic effects of mutant spastin protein cause different FAT deficits that are mediated by casein kinase 2 (CK2), and these deficits promote corticospinal axon degeneration (gain-of-function). The former makes the axon more vulnerable, but it is the latter that suffices for corticospinal axon degeneration. The proposed work seeks to test these hypotheses by directly comparing a mouse model with a single SPAST allele (SPAST +/-) with a transgenic mouse model with both endogenous mouse SPAST alleles intact that additionally expresses human spastin bearing a pathogenic mutation associated with SPG4-HSP (spastin-C448Y mice). In Aim 1, these models will be individually crossed with mice that selectively express eGFP in corticospinal motor neurons (CSMN), so that loss-of and gain-of-function contributions to the disease can be investigated. In Aim 2, FAT deficits will be studied in neurons cultured from these animals, and specific hypotheses for the etiology of the deficits will be tested. In Aim 3, studies are proposed using transgenic spastin-C448Y mice in which autophagy is experimentally enhanced or CK2 levels are experimentally reduced, to test the hypothesis that these manipulations will prevent or reduce corticospinal axon degeneration and associated behavioral deficits. The overall significance of this project is to establish mechanisms underlying SPG4-HSP and forge a path toward effective therapies for patients.

项目摘要/摘要