Molecular Cell
Volume 78, Issue 2, 16 April 2020, Pages 329-345.e9
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Article
Differentiation Drives Widespread Rewiring of the Neural Stem Cell Chaperone Network

https://doi.org/10.1016/j.molcel.2020.03.009Get rights and content
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Highlights

  • NPSC differentiation alters proteostasis strategies by rewiring chaperone network

  • High TRiC/CCT in NSPCs promotes proteome solubility and stress resilience

  • sHSP induced in neural progeny detoxify misfolded proteins by spatial sequestration

  • Widespread decline in TRiC/CCT levels and NSPC proteostasis in brain aging

Summary

Neural stem and progenitor cells (NSPCs) are critical for continued cellular replacement in the adult brain. Lifelong maintenance of a functional NSPC pool necessitates stringent mechanisms to preserve a pristine proteome. We find that the NSPC chaperone network robustly maintains misfolded protein solubility and stress resilience through high levels of the ATP-dependent chaperonin TRiC/CCT. Strikingly, NSPC differentiation rewires the cellular chaperone network, reducing TRiC/CCT levels and inducing those of the ATP-independent small heat shock proteins (sHSPs). This switches the proteostasis strategy in neural progeny cells to promote sequestration of misfolded proteins into protective inclusions. The chaperone network of NSPCs is more effective than that of differentiated cells, leading to improved management of proteotoxic stress and amyloidogenic proteins. However, NSPC proteostasis is impaired by brain aging. The less efficient chaperone network of differentiated neural progeny may contribute to their enhanced susceptibility to neurodegenerative diseases characterized by aberrant protein misfolding and aggregation.

Keywords

neural stem cells
NSPC
proteostasis
protein quality control
TRiC/CCT
HSPB5
CRYAB
protein aggregation
aging
neurodegeneration

Cited by (0)

7

Present address: Princess Máxima Center for Pediatric Oncology, ONCODE Institute, Utrecht, the Netherlands

8

These authors contributed equally

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