遗传性痉挛性截瘫11型发病机制研究进展

Research advances in the pathogenesis of hereditary spastic paraplegia type 11

摘要:

遗传性痉挛性截瘫11型（SPG11）是最常见的常染色体隐性遗传性痉挛性截瘫（AR-HSP）亚型，由SPG11基因突变所致，其临床特点为进行性痉挛性截瘫、认知功能减退、构音障碍、周围神经病、肌萎缩、括约肌功能障碍和共济失调。影像学特点为胼胝体变薄和脑室周围白质改变。近年来分子遗传学研究表明，神经免疫炎症反应、胆固醇转运障碍、线粒体功能与动力学异常、轴突运输缺陷、自噬与溶酶体通路损伤、神经发育障碍及下丘脑代谢失衡等7个方面参与了SPG11的发病机制，这些机制不仅揭示了SPG11疾病的致病基础，还为开发针对SPG11相关HSP的靶向治疗策略提供了重要的理论依据。该文将就此进行综述并展望未来治疗方向。

Abstract:

Hereditary spastic paraplegia type 11 （SPG11） is the most common subtype of autosomal recessive hereditary spastic paraplegia （HSP） and is caused by mutations in the SPG11 gene， with the clinical features of progressive spastic paraparesis， cognitive decline， dysarthria， peripheral neuropathy， muscle atrophy， sphincter dysfunction， and ataxia. Typical neuroimaging features include thinning of the corpus callosum and periventricular white matter abnormalities. Molecular genetic research in recent years has shown that the pathogenesis of SPG11 involves at least seven interrelated mechanisms， i.e.， neuroimmune and inflammatory responses， impaired cholesterol transport， abnormal mitochondrial function and dynamics， defects in axonal transport， disruption of the autophagy-lysosome pathway， neurodevelopmental disorders， and metabolic imbalance in the hypothalamus. These mechanisms not only clarify the pathogenic basis of SPG11， but also provide important theoretical support for the development of targeted therapeutic strategies for SPG11-associated HSP. This article reviews these mechanisms and explore future therapeutic directions.