Human HSPB1 mutation recapitulates features of distal hereditary motor neuropathy (dHMN) in Drosophila

Biochem Biophys Res Commun. 2020 Jan 1;521(1):220-226. doi: 10.1016/j.bbrc.2019.10.110. Epub 2019 Oct 17.

Abstract

Distal hereditary motor neuropathies (dHMN) are a group of inherited peripheral nerve disorders characterized by length-dependent motor neuron weakness and subsequent muscle atrophy. Missense mutations in the gene encoding small heat shock protein HSPB1 (HSP27) have been associated with hereditary neuropathies including dHMN. HSPB1 is a member of the small heat shock protein (sHSP) family characterized by a highly conserved α-crystallin domain that is critical to their chaperone activity. In this study, we modeled HSPB1 mutant-induced neuropathies in Drosophila using a human HSPB1S135F mutant that has a missense mutation in its α-crystallin domain. Overexpression of the HSPB1 mutant produced no significant defect in the Drosophila development, however, a partial reduction in the life span was observed. Further, the HSPB1 mutant gene induced an obvious loss of motor activity when expressed in Drosophila neurons. Moreover, suppression of histone deacetylase 6 (HDAC6) expression, which has critical roles in HSPB1 mutant-induced axonal defects, successfully rescued the motor defects in the HSPB1 mutant Drosophila model.

Keywords: Charcot-Marie-Tooth disease; Distal hereditary motor neuropathies; Drosophila; HDAC6; HSPB1; Small heat shock protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Drosophila melanogaster / genetics*
  • Heat-Shock Proteins / genetics*
  • Heat-Shock Proteins / metabolism
  • Hereditary Sensory and Motor Neuropathy / genetics*
  • Hereditary Sensory and Motor Neuropathy / metabolism
  • Humans
  • Molecular Chaperones / genetics*
  • Molecular Chaperones / metabolism
  • Motor Activity / genetics
  • Mutation
  • alpha-Crystallins / genetics
  • alpha-Crystallins / metabolism

Substances

  • HSPB1 protein, human
  • Heat-Shock Proteins
  • Molecular Chaperones
  • alpha-Crystallins