遗传性痉挛性截瘫4型发病机制的研究进展

Progress of pathogenesis of hereditary spastic paraplegia type 4

遗传性痉挛性截瘫(HSP)是一类具有显著临床和遗传异质性的神经退行性疾病,主要临床表现为缓慢进展的双下肢无力和痉挛性截瘫,其中以痉挛性截瘫4型(SPG4)最为常见。迄今,已发现78个HSP致病基因相关位点,59个致病基因被克隆。基因SPAST编码的微管切割蛋白(spastin)对于调节微管长度、数量和活力,以及对各种细胞器的发生、发展都具有重要意义。过去认为SPAST基因突变导致所编码的蛋白功能部分或全部丧失,是疾病发生的主要机制。目前认为,SPAST基因编码的2种异构体(M1、M87)可能存在获得性的突变蛋白的神经毒性作用,也是重要致病机制之一。该文就SPG4的发病机制进行综述。

Hereditary spastic paraplegia （HSP） is a group of significantly clinically and genetically heterogeneous neurodegenerative disorders, which are predominantly characterized by progressive lower limbs weakness and spasticity, and spastic paraplegia type 4 （SPG4） is the most common type among them. So far, mutations in 78 distinct loci and 59 mutated genes have been identified in patients with HSE The protein spastin coded by the SPAST gene plays a critical role in regulating length, number and activity of microtubules, as well as the occurrence and development of various organelles. It is generally believed that the mutated spastin leads to partial or total loss of the function, which is the main pathogenetic mechanism. While recent studies have also suggested that there may exist acquired neurotoxic effects of mutant proteins by the two isoforms （M1, M87） coded by the SPAST gene, which is also one of the critical mechanisms. In this paper, the pathogenesis of SPG4 was reviewed.