Overexpression of mutant HSP27 causes axonal neuropathy in mice
Jinho Lee1, Sung-Chul Jung2, Jaesoon Joo1
1Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.
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.
Insights
Mutant heat shock 27 kDa protein 1 (HSP27) causes peripheral neuropathy. This new mouse model aids research into treatments for distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease type 2 F (CMT2F).
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Mutations in heat shock 27 kDa protein 1 (HSP27 or HSPB1) are linked to distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease type 2 F (CMT2F).
- Mutant HSP27 proteins disrupt axonal transport by decreasing acetylated tubulin levels.
Purpose of the Study:
- To develop and characterize a transgenic mouse model overexpressing a mutant HSP27-S135F protein.
- To investigate the phenotypic effects of HSP27-S135F overexpression on motor function and peripheral nerves.
Main Methods:
- Generation of transgenic mice using the Cytomegalovirus (CMV) immediate early promoter.
- Phenotypic analysis including behavioral tests (Rotarod), MRI, electrophysiology (CMAP, MNCV), and sciatic nerve pathology (Toluidine blue, electron microscopy, immunohistochemistry).
Main Results:
- Transgenic mice exhibited motor neuropathy, reduced motor performance, and fatty infiltration in calf muscles.
- Electrophysiological studies showed reduced compound muscle action potential (CMAP) but normal motor nerve conduction velocity (MNCV).
- Sciatic nerves displayed reduced large myelinated axons, aberrant myelination, elevated phosphorylated neurofilaments, and decreased acetylated tubulin.
Conclusions:
- Overexpression of HSP27-S135F induces peripheral neuropathy, mirroring dHMN/CMT2F phenotypes.
- This mouse model is valuable for studying therapeutic strategies for HSP27-related neuropathies.
