Overexpression of mutant HSP27 causes axonal neuropathy in mice

Journal of Biomedical Science

Byung-Ok Choi³  Young Bin Hong⁵  Ji Yon Kim¹  So-Youn Woo¹  Jingeun Rheey²  Sunhee Hwang⁶  Namhee Jung⁴  Hye-Jee Ahn⁶  Ji-Su Lee⁶  Ha Kyung Yeo⁶  Geon Kwak⁶  Hyo Won Moon⁶  Yu-Ri Choi⁴  Jaesoon Joo⁶  Sung-Chul Jung⁴  Jinho Lee⁶ 

[1] Microbiology, Ewha Womans University School of Medicine, Seoul, Korea;Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Seoul, Korea;Neuroscience center, Samsung Medical Center, Seoul, Korea;Department of Biochemistry, Ewha Womans University School of Medicine, Seoul, Korea;Stem Cell & Regenerative Medicine Center, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu 135-710, Seoul, Korea;Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu 135-710, Seoul, Korea

关键词: Magnetic resonance image (MRI);    Mouse model;    Axonopathy;    Distal hereditary motor neuropathy (dHMN);    Charcot-Marie-Tooth disease (CMT);    kDa protein 1 (HSP27 or HSPB1);    Heat shock 27 ;   

Others  :  1219656
DOI  :  10.1186/s12929-015-0154-y

 received in 2015-03-02, accepted in 2015-06-11,  发布年份 2015

【 摘 要 】

Background

Mutations in heat shock 27 kDa protein 1 (HSP27 or HSPB1) cause distal hereditary motor neuropathy (dHMN) or Charcot-Marie-Tooth disease type 2 F (CMT2F) according to unknown factors. Mutant HSP27 proteins affect axonal transport by reducing acetylated tubulin.

Results

We generated a transgenic mouse model overexpressing HSP27-S135F mutant protein driven by Cytomegalovirus (CMV) immediate early promoter. The mouse phenotype was similar to dHMN patients in that they exhibit motor neuropathy. To determine the phenotypic aberration of transgenic mice, behavior test, magnetic resonance imaging (MRI), electrophysiological study, and pathology were performed. Rotarod test showed that founder mice exhibited lowered motor performance. MRI also revealed marked fatty infiltration in the anterior and posterior compartments at calf level. Electrophysiologically, compound muscle action potential (CMAP) but not motor nerve conduction velocity (MNCV) was reduced in the transgenic mice. Toluidine staining with semi-thin section of sciatic nerve showed the ratio of large myelinated axon fiber was reduced, which might cause reduced locomotion in the transgenic mice. Electron microscopy also revealed abundant aberrant myelination. Immunohistochemically, neuronal dysfunctions included elevated level of phosphorylated neurofilament and reduced level of acetylated tubulin in the sural nerve of transgenic mice. There was no additional phenotype besides motor neuronal defects.

Conclusions

Overexpression of HSP27-S135F protein causes peripheral neuropathy. The mouse model can be applied to future development of therapeutic strategies for dHMN or CMT2F.

【 授权许可】

   
2015 Lee et al.

【 图 表 】

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