Details

Autor(en) / Beteiligte

• Vonk, Willianne I.M.
• Rainbolt, T. Kelly
• Dolan, Patrick T.
• Webb, Ashley E.
• Brunet, Anne
• Frydman, Judith

Titel

Differentiation Drives Widespread Rewiring of the Neural Stem Cell Chaperone Network

Ist Teil von

• Molecular cell, 2020-04, Vol.78 (2), p.329-345.e9

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek

Beschreibungen/Notizen

• 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. [Display omitted] •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 Differentiation of neural stem cells (NSPCs) rewires cellular chaperone networks, fundamentally changing cellular proteostasis strategies. Chaperonin TRiC/CCT, high in NSPCs, promotes stress resilience and cellular fitness. Differentiation lowers TRiC/CCT and induces sHSPs, which promote misfolded protein sequestration into protective inclusions. Aging attenuates TRiC/CCT and NSPC proteostasis, likely contributing to proteinopathies.