CHIP-dependent regulation of the actin cytoskeleton is linked to neuronal cell membrane integrity

CHIP is an E3-ubiquitin ligase that contributes to healthy aging and has been characterized as neuroprotective. To elucidate dominant CHIP-dependent changes in protein steady-state levels in a patient-derived human neuronal model, CHIP function was ablated using gene-editing and an unbiased proteomic analysis conducted to compare knock-out and wild-type isogenic induced pluripotent stem cell (iPSC)-derived cortical neurons. Rather than a broad effect on protein homeostasis, loss of CHIP function impacted on a focused cohort of proteins from actin cytoskeleton signaling and membrane integrity networks. In support of the proteomics, CHIP knockout cells had enhanced sensitivity to induced membrane damage. We conclude that the major readout of CHIP function in cortical neurons derived from iPSC of a patient with elevate a-synuclein, Parkinson's disease and dementia, is the modulation of substrates involved in maintaining cellular health''. Thus, regulation of the actin cytoskeletal and membrane integrity likely contributes to the neuroprotective function(s) of CHIP.

Automated summary

CHIP, an E3-ubiquitin ligase, plays a crucial role in healthy aging and neuroprotection. A study on patient-derived human neuronal model revealed that loss of CHIP function primarily affects a focused group of proteins related to actin cytoskeleton signaling and membrane integrity networks. Knockout cells without CHIP showed increased sensitivity to induced membrane damage, indicating that modulation of substrates involved in maintaining cellular health contributes to the neuroprotective functions of CHIP.