Another potential mechanism in SPG4

Toxic effect rather than shortage in some cases

Certain SPAST mutations do not act through reduced Spastin levels. In such cases, Spastin may damage the corticospinal tracts through a toxic effect from one of its different forms (isoforms).

Background: Haploinsufficiency is widely accepted as the pathogenic mechanism of spastic paraplegia type 4 (SPG4). However, there are some cases that cannot be explained by reduced function of the spastin protein encoded by SPAST.

Objectives: To identify the causative gene of autosomal dominant hereditary spastic paraplegia in three large Chinese families and explore the pathological mechanism of a spastin variant.

Methods: Three large Chinese hereditary spastic paraplegia families with a total of 247 individuals (67 patients) were investigated, of whom 59 members were recruited to the study. Genetic testing was performed to identify the causative gene. Western blotting and immunofluorescence were used to analyze the effects of the mutant proteins in vitro.

Results: In the three hereditary spastic paraplegia families, of whom three index cases were misdiagnosed as other types of neurological diseases, a novel c.985dupA (p.Met329Asnfs*3) variant in SPAST was identified and was shown to cosegregate with the phenotype in the three families. The c.985dupA mutation produced two truncated mutants (mutant M1 and M87 isoforms) that accumulated to a higher level than their wild-type counterparts. Furthermore, the mutant M1 isoform heavily decorated the microtubules and rendered them resistant to depolymerization. In contrast, the mutant M87 isoform was diffusely localized in both the nucleus and the cytoplasm, could not decorate microtubules, and was not able to promote microtubule disassembly.

Conclusions: SPAST mutations leading to premature stop codons do not always act through haploinsufficiency. The truncated spastin may damage the corticospinal tracts through an isoform-specific toxic effect.

SOURCE:  Mov Disord. 2022 Mar;37(3):598-607. doi: 10.1002/mds.28885. Epub 2021 Dec 20. PMID: 34927746 © 2021 The Authors.

A Novel SPAST Mutation Results in Spastin Accumulation and Defects in Microtubule Dynamics

Rui Chen  1 Shiyue Du  1 Yanyi Yao  2 Lu Zhang  1 Junyu Luo  1 Yinhua Shen  1 Zhenping Xu  3 Xiaomei Zeng  1 Luoying Zhang  1 Mugen Liu  1 Chuang Yin  4 Beisha Tang  5 Jun Tan  4 Xuan Xu  6 Jing Yu Liu  6

1. College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, China.                                                                                                                  

2. Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province, Wuhan, China.                                                                                                                            

3. College of Life Science and Technology, Xinxiang Medical University, Xinxiang, China.                                                                                    

4.  Department of Neurology, Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.                          

5.  Department of Neurology, Xiangya Hospital, Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China.                                                                                  

6.  Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.

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