DNAJB6, a Key Factor in Neuronal Sensitivity to Amyloidogenesis

Mol Cell. 2020 Apr 16;78(2):346-358.e9. doi: 10.1016/j.molcel.2020.02.022. Epub 2020 Apr 7.


CAG-repeat expansions in at least eight different genes cause neurodegeneration. The length of the extended polyglutamine stretches in the corresponding proteins is proportionally related to their aggregation propensity. Although these proteins are ubiquitously expressed, they predominantly cause toxicity to neurons. To understand this neuronal hypersensitivity, we generated induced pluripotent stem cell (iPSC) lines of spinocerebellar ataxia type 3 and Huntington's disease patients. iPSC generation and neuronal differentiation are unaffected by polyglutamine proteins and show no spontaneous aggregate formation. However, upon glutamate treatment, aggregates form in neurons but not in patient-derived neural progenitors. During differentiation, the chaperone network is drastically rewired, including loss of expression of the anti-amyloidogenic chaperone DNAJB6. Upregulation of DNAJB6 in neurons antagonizes glutamate-induced aggregation, while knockdown of DNAJB6 in progenitors results in spontaneous polyglutamine aggregation. Loss of DNAJB6 expression upon differentiation is confirmed in vivo, explaining why stem cells are intrinsically protected against amyloidogenesis and protein aggregates are dominantly present in neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloidogenic Proteins / genetics*
  • Cell Differentiation / genetics*
  • Gene Expression Regulation / genetics
  • Gene Knockout Techniques
  • Glutamic Acid / metabolism
  • HSP40 Heat-Shock Proteins / genetics*
  • Humans
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Huntington Disease / pathology
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology
  • Machado-Joseph Disease / genetics
  • Machado-Joseph Disease / metabolism
  • Machado-Joseph Disease / pathology
  • Molecular Chaperones / genetics*
  • Nerve Tissue Proteins / genetics*
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Protein Aggregates / genetics
  • Trinucleotide Repeat Expansion / genetics


  • Amyloidogenic Proteins
  • DNAJB6 protein, human
  • HSP40 Heat-Shock Proteins
  • Molecular Chaperones
  • Nerve Tissue Proteins
  • Protein Aggregates
  • Glutamic Acid