期刊
HUMAN MOLECULAR GENETICS
卷 31, 期 11, 页码 1844-1859出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddab367
关键词
-
资金
- NIH [R01NS115977, R01NS118177, R01NS28785, R21AG068597]
- Lisa Dean Moseley Foundation
- Spastic Paraplegia Foundation
- Pennsylvania Department of Health Commonwealth Universal Research Enhancement program via Drexel University College of Medicine (CURE Grant SAP) [4100062203]
- Advanced Scholarship for Research into Hereditary Spastic Paraplegia and Related Diseases from the Tom Wahlig Foundation
- Deutsche Forschungsgemeinschaft (German Research Foundation) [KN556/11-2, KN556/12-1]
- Landesforschungsforderung Hamburg (Research Funds of the Federal State of Hamburg) [FV76]
Hereditary spastic paraplegia (HSP) is a neurodegenerative disease characterized by degeneration of corticospinal tracts and axonal swellings leading to gait deficiencies. The most common form of HSP, SPG4-HSP, is caused by mutations in the spastin gene (SPAST). This study demonstrates that crossbreeding mice with axonal swellings but no gait deficiencies and mice with gait deficiencies but no axonal swellings results in offspring with both axonal swellings and worsened gait deficiencies, providing a valuable model for studying the disease pathology and testing potential therapies for SPG4-HSP.
Hereditary spastic paraplegia (HSP) is a disease in which dieback degeneration of corticospinal tracts, accompanied by axonal swellings, leads to gait deficiencies. SPG4-HSP, the most common form of the disease, results from mutations of human spastin gene (SPAST), which is the gene that encodes spastin, a microtubule-severing protein. The lack of a vertebrate model that recapitulates both the etiology and symptoms of SPG4-HSP has stymied the development of effective therapies for the disease. hSPAST-C448Y mice, which express human mutant spastin at the ROSA26 locus, display corticospinal dieback and gait deficiencies but not axonal swellings. On the other hand, mouse spastin gene (Spast)-knockout (KO) mice display axonal swellings but not corticospinal dieback or gait deficiencies. One possibility is that reduced spastin function, resulting in axonal swellings, is not the cause of the disease but exacerbates the toxic effects of the mutant protein. To explore this idea, Spast-KO and hSPAST-C448Y mice were crossbred, and the offspring were compared with the parental lines via histological and behavioral analyses. The crossbred animals displayed axonal swellings as well as earlier onset, worsened gait deficiencies and corticospinal dieback compared with the hSPAST-C448Y mouse. These results, together with observations on changes in histone deacetylases 6 and tubulin modifications in the axon, indicate that each of these three transgenic mouse lines is valuable for investigating a different component of the disease pathology. Moreover, the crossbred mice are the best vertebrate model to date for testing potential therapies for SPG4-HSP.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据