Mutant HSPB8 causes protein aggregates and a reduced mitochondrial membrane potential in dermal fibroblasts from distal hereditary motor neuropathy patients

Neuromuscul Disord. 2012 Aug;22(8):699-711. doi: 10.1016/j.nmd.2012.04.005. Epub 2012 May 15.


Missense mutations in the small heat shock protein HSPB8 cause distal hereditary motor neuropathy (dHMN) and axonal Charcot-Marie-Tooth disease (CMT2L). We previously demonstrated that, despite the ubiquitous expression of HSPB8, motor neurons appear to be predominantly affected by HSPB8 mutations. Here, we studied the effect of mutant HSPB8 in primary fibroblast cultures derived from dHMN patients' skin biopsy. In early passage cultures, we observed in all patients' fibroblasts HSPB8 protein aggregates that were not detected in control cells. After applying heat shock stress on the patients' early passage cultured cells, the protein aggregates coalesced into larger formations, while in control cells a homogenous upregulation of HSPB8 protein expression was seen. We also found a reduction in the mitochondrial membrane potential in the early passage cultures. After three months in culture, the number of cells with aggregates had become indistinguishable from that in controls and the mitochondrial membrane potential had returned to normal. These results emphasize the possible drawbacks of using patients' non-neuronal cells to study neuropathological disease mechanisms.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Apoptosis
  • Axons / pathology
  • Biomarkers / metabolism
  • Biopsy
  • Cells, Cultured
  • Female
  • Fibroblasts / pathology
  • Fibroblasts / physiology*
  • Heat-Shock Proteins / genetics*
  • Humans
  • Male
  • Membrane Potential, Mitochondrial / physiology*
  • Middle Aged
  • Molecular Chaperones
  • Motor Neuron Disease / pathology*
  • Motor Neuron Disease / physiopathology*
  • Mutation, Missense / genetics*
  • Protein Binding
  • Protein Serine-Threonine Kinases / genetics*
  • Proteins / metabolism*
  • Skin / pathology


  • Biomarkers
  • HSPB8 protein, human
  • Heat-Shock Proteins
  • Molecular Chaperones
  • Proteins
  • Protein Serine-Threonine Kinases