Modeling gain-of-function and loss-of-function components of SPAST-based hereditary spastic paraplegia using transgenic mice.
Modeling gain-of-function and loss-of-function components of SPAST-based hereditary spastic paraplegia using transgenic mice.
复制标题
使用转基因小鼠对基于 SPAST 的遗传性痉挛性截瘫的功能获得和功能丧失成分进行建模。
DOI：
10.1093/hmg/ddab367
复制
发表时间：
2022
影响因子：
3.5
通讯作者：
Qiang,Liang
中科院分区：
文献类型：
--
作者：
Piermarini,Emanuela;Akarsu,Seyma;Connors,Theresa;Kneussel,Matthias;Lane,MichaelA;Morfini,Gerardo;Karabay,Arzu;Baas,PeterW;Qiang,Liang
遗传性痉挛性截瘫（Hereditary spastic paraplegia，HSP）是一种以皮质脊髓束退行性变为特征，伴有轴索损伤的步态障碍性疾病，其中最常见的SPG 4-HSP是由编码微管断裂蛋白spastin的人类spastin基因（human spastin gene，SPAST）突变引起的。缺乏一种能概括SPG 4-HSP的病因和症状的脊椎动物模型，阻碍了该病有效治疗方法的发展。hSPAST-C448 Y小鼠在ROSA 26位点表达人突变型痉挛素，表现出皮质脊髓死亡和步态缺陷，但不表现出轴突萎缩。另一方面，小鼠痉挛素基因（Stast）敲除（KO）小鼠显示轴突萎缩，但不显示皮质脊髓死亡或步态缺陷。一种可能性是，导致轴突痉挛的痉挛素功能降低不是疾病的原因，但加剧了突变蛋白的毒性作用。为了探索这一想法，Spast-KO和hSPAST-C448 Y小鼠杂交，并通过组织学和行为分析将后代与亲本系进行比较。与hSPAST-C448 Y小鼠相比，杂交动物显示轴突萎缩以及更早的发作、恶化的步态缺陷和皮质脊髓死亡。这些结果，连同观察组蛋白脱乙酰基酶6和微管蛋白的轴突中的修改的变化，表明这三个转基因小鼠系的每一个是有价值的研究疾病病理的不同组成部分。此外，杂交小鼠是迄今为止测试SPG 4-HSP潜在疗法的最佳脊椎动物模型。
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 ofSPG4-HSP has stymied the development of effective therapies for the disease. hSPAST-C448Y mice, which express human mutant spastin at theROSA26locus, 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 forSPG4-HSP.