Overexpression of mutant HSP27 causes axonal neuropathy in mice

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.

Small heat shock proteins in ageing and age-related diseases

“…The recent generation of mouse models has provided novel insights concerning the relation between HSP mutations and CMT. Overexpression of either mutant HSPB1 S135F or HSPB1 P182L isoforms in the neuronal system leads to pronounced motor defects and reduced muscle strength, as monitored through behavioural tests (d'Ydewalle et al 2011;Lee et al 2015). While there is support for aberrant myelination in the latter study using the HSPB1 S135F model, a decrease in the levels of a-tubulin acetylation seems to be a common denominator of the observed pathology.…”

Late onset dHMN II caused by c.404C>G mutation in HSPB1 gene

“…The c.404C>G mutation is located in the α‐crystallin domain (d'Ydewalle et al , ) . This domain is related to mitochondrial movement, which is important to maintain the integrity of cellular cytoskeleton transport (Lee et al , ) . The mutation may lead to loss of the cytoskeleton stabilizing role of HSPB1, a known pathogenic pathway associated with neuronal degeneration (Bonini et al , ) .…”

“…The mutation may lead to loss of the cytoskeleton stabilizing role of HSPB1, a known pathogenic pathway associated with neuronal degeneration (Bonini et al , ) . Overexpression of HSPB1‐S135F mutant protein reproduces motor neuropathy in mice (Lee et al , ) and leads to progressive degeneration of primary cultured mouse motor neurons associated with a disruption of neurofilament network (Zhai et al , ) .…”

Pilot phenotype and natural history study of hereditary neuropathies caused by mutations in the HSPB1 gene

“…Four mutant HSPB1 transgenic mouse models of dHMN have now been developed [8], [9], [10] and in 2011, d'Ydewalle et al. observed that treatment with a selective HDAC6 inhibitor successfully reversed the clinical phenotype of both S135F and P182L transgenic mice [8].…”