CHIP is an E3-ubiquitin ligase that contributes to healthy aging and has been characterised 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 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 signalling and membrane integrity networks. In support of the proteomics, CHIP knock-out 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 -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.