Progress in research on the pathogenic mechanism of hereditary spastic paraplegia

On December 20, Movement Disorders published a research paper entitled A Novel SPAST Mutation Results in Spastin Accumulation and Defects in Microtubule Dynamics online.
Completed by Liu Jingyu's research group at the State Key Laboratory of Science
.

The study carried out linkage analysis and Sanger sequencing of genetic disease families, combined with cell line model analysis, and found that the truncated protein spastin encoded by the pathogenic gene SPAST of hereditary spastic paraplegia (HSP) can interfere with microbes in an isoform-specific manner.
The dynamic balance of the tube leads to the occurrence of HSP
.

The study further proposed that the truncated mutant of spastin may affect the function of the corticospinal tract through long-term cell accumulation, which provides a new direction for exploring the pathogenic mechanism and treatment of hereditary spastic paraplegia type 4 (SPG4)
.

Hereditary spastic paraplegia is a genetic and clinically heterogeneous neurodegenerative disease whose main characteristics are progressive spasm and weakness of the lower limbs
.

Spastic paraplegia type 4 caused by mutations in the SPAST gene is a common HSP subtype with autosomal dominant inheritance
.

At present, it is generally believed that haploinsufficiency caused by the loss of protein function caused by the mutation of this gene is the pathogenic mechanism of the disease, but this theory fails to clarify the clinical phenotype of spastic paraplegia and the degree of functional damage of the mutant protein.
Correlation between, and the corresponding clinical intervention treatment progress is relatively slow
.

SPAST gene mainly encodes two isomers of M1 (68 kDa) and M87 (60 kDa) and exerts microtubule shearing activity to maintain the dynamic balance of microtubules
.

The research team collected three large hereditary spastic paraplegia families (247 members, 67 patients) from six natural villages in the early stage (Figure 1).
Through linkage analysis, the pathogenic segments of the three families were simultaneously mapped to the SPAST gene.
Block, further Sanger sequencing confirmed that all patients carry a new SPAST insertion mutation c.
985dupA (p.
Met329Asnfs*3), this mutation produces two truncated isoforms dupA-M1 and dupA-M87, these two The protein degradation rate of the mutant is reduced
.

At the same time, the study also found that dupA-M1 is tightly bound to microtubules (fibrous distribution in the cell), and blocks the depolymerization process of microtubules; while dupA-M87 is evenly distributed in the cytoplasm and nucleus, not showing Interference to the depolymerization of microtubules (Figure 2A)
.

The study found that the spastin truncated body caused by the SPAST mutation can accumulate in the cell for a long time, or cause cytotoxicity in the corticospinal tract and its distal axons that highly express spastin
.

In addition, the study revealed to some extent that the mutant spastin may affect the function of the corticospinal tract in an isoform-specific manner, leading to hereditary spastic paraplegia (Figure 2B)
.

However, its specific mechanism needs to be further explored
.

The research work was funded by the National Natural Science Foundation of China, the Ministry of Science and Technology, and Shanghai
.

Researchers from Huazhong University of Science and Technology and Hubei Maternity and Child Health Hospital participated in this work
.

Figure 1.
Three pedigrees of spastic paraplegia with autosomal dominant inheritance from the same ancestor Figure 2.
(A) Wild type (WT-M1 and WT-M87) and truncated body (dupA-M1 and dupA-M87) ) Cellular localization of protein; (B) The pathogenesis hypothesis of spastin mutant c.
985dupA (p.
Met329Asnfs*3).
Source: Center for Excellence in Brain Science and Intelligent Technology, Chinese Academy of Sciences