CHIP-dependent regulation of the actin cytoskeleton is linked to neuronal cell membrane integrity
Catarina Dias,
Erisa Nita,
Jakub Faktor,
Ailish C. Tynan,
Lenka Hernychova,
Borivoj Vojtesek,
Jesper Nylandsted,
Ted R. Hupp,
Tilo Kunath,
Kathryn L. Ball
Affiliations
Catarina Dias
Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK; Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, The University of Edinburgh, Edinburgh EH16 4UU, UK
Erisa Nita
Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
Jakub Faktor
Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic; University of Gdansk, International Centre for Cancer Vaccine Science, 80-822 Gdansk, Poland
Ailish C. Tynan
Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
Lenka Hernychova
Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
Borivoj Vojtesek
Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
Jesper Nylandsted
Membrane Integrity Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
Ted R. Hupp
Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK; University of Gdansk, International Centre for Cancer Vaccine Science, 80-822 Gdansk, Poland
Tilo Kunath
Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, The University of Edinburgh, Edinburgh EH16 4UU, UK
Kathryn L. Ball
Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK; Corresponding author
Summary: 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 α-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.
