title: Overexpression of mutant HSP27 causes axonal neuropathy in mice.
abstract: 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.
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.
authors.forename: Jinho
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: Sung-Chul
authors.initials: SC
authors.lastname: Jung
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.
authors.forename: Jaesoon
authors.initials: J
authors.lastname: Joo
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.|Department of Biochemistry, Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: Yu-Ri
authors.initials: YR
authors.lastname: Choi
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.
authors.forename: Hyo Won
authors.initials: HW
authors.lastname: Moon
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.
authors.forename: Geon
authors.initials: G
authors.lastname: Kwak
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.
authors.forename: Ha Kyung
authors.initials: HK
authors.lastname: Yeo
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.
authors.forename: Ji-Su
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.
authors.forename: Hye-Jee
authors.initials: HJ
authors.lastname: Ahn
authors.affiliation: Department of Biochemistry, Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: Namhee
authors.initials: N
authors.lastname: Jung
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea.
authors.forename: Sunhee
authors.initials: S
authors.lastname: Hwang
authors.affiliation: Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Seoul, Korea.
authors.forename: Jingeun
authors.initials: J
authors.lastname: Rheey
authors.affiliation: Microbiology, Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Woo
authors.affiliation: Microbiology, Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: Ji Yon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Stem Cell & Regenerative Medicine Center, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea. youngbinhong@gmail.com.
authors.forename: Young Bin
authors.initials: YB
authors.lastname: Hong
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Korea. bochoi77@hanmail.net.|Neuroscience center, Samsung Medical Center, Seoul, Korea. bochoi77@hanmail.net.
authors.forename: Byung-Ok
authors.initials: BO
authors.lastname: Choi
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000503:physiopathology
chemical_list: D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; D018832:Molecular Chaperones; D009363:Neoplasm Proteins