Abstract
BackgroundMutations 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.ResultsWe 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.ConclusionsOverexpression of HSP27-S135F protein causes peripheral neuropathy. The mouse model can be applied to future development of therapeutic strategies for dHMN or CMT2F.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-015-0154-y) contains supplementary material, which is available to authorized users.
Highlights
Mutations in heat shock 27 kDa protein 1 (HSP27 or HSPB1) cause distal hereditary motor neuropathy or Charcot-Marie-Tooth disease type 2 F (CMT2F) according to unknown factors
Heat shock 27 kDa protein 1 (HSP27) is located in chromosome 7q11-q21 and encodes a 27 kDa protein possessing an α-crystallin domain [5]
HSP27-S135F transgenic mice exhibit reduced motor function Wild type and S135F mutant HSP27 gene was cloned as described in Materials and Methods
Summary
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. Mutations in heat shock 27 kDa protein 1 (HSP27, called HSPB1) are associated with hereditary peripheral neuropathy [1,2,3,4]. Mutation in HSP27 deteriorates axonal transport in the peripheral nervous system [15]. Mutant HSP27 protein reduces neuronal cell viability and impairs neurofilament assembly [1, 16]. The expression of mutant HSP27 reduces acetylated α-tubulin in dorsal root
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