Molecular Cell
Volume 78, Issue 2, 16 April 2020, Pages 346-358.e9
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Article
DNAJB6, a Key Factor in Neuronal Sensitivity to Amyloidogenesis

https://doi.org/10.1016/j.molcel.2020.02.022Get rights and content
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Highlights

  • The chaperone network rewires during differentiation

  • Endogenous expanded ataxin-3 aggregates in patient-derived neurons but not progenitors

  • DNAJB6 is critical for polyglutamine protein aggregation in patient-derived cells

Summary

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.

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