@article{c1b8932c642a45fca2089141231b3382,
title = "Proteomic analysis of human iPSC-derived sensory neurons implicates cell stress and microtubule dynamics dysfunction in bortezomib-induced peripheral neurotoxicity",
abstract = "The neurotoxic effects of the chemotherapeutic agent bortezomib on dorsal root ganglia sensory neurons are well documented, yet the mechanistic underpinnings that govern these cellular processes remain incompletely understood. In this study, system-wide proteomic changes were identified in human induced pluripotent stem cell-derived sensory neurons (iSNs) exposed to a clinically relevant dose of bortezomib. Label-free mass spectrometry facilitated the identification of approximately 2800 iSN proteins that exhibited differential levels in the setting of bortezomib. A significant proportion of these proteins affect the cellular processes of microtubule dynamics, cytoskeletal and cytoplasmic organization, and molecular transport, and pathway analysis revealed an enrichment of proteins in signaling pathways attributable to the unfolded protein response and the integrated stress response. Alterations in microtubule-associated proteins suggest a multifaceted relationship exists between bortezomib-induced proteotoxicity and microtubule cytoskeletal architecture, and MAP2 was prioritized as a topmost influential candidate. We observed a significant reduction in the overall levels of MAP2c in somata without discernable changes in neurites. As MAP2 is known to affect cellular processes including axonogenesis, neurite extension and branching, and neurite morphology, its altered levels are suggestive of a prominent role in bortezomib-induced neurotoxicity.",
keywords = "Bortezomib, Cytoskeletal dynamics, ISR, MAP2, Neuropathy, Neurotoxicity, Proteomics, Sensory neurons, UPR",
author = "{Nathan P. Staff} and Hrstka, {Sybil C.L.} and Soneela Ankam and Busra Agac and Klein, {Jon P.} and Moore, {Raymond A.} and Bhavya Narapureddy and Isabella Schneider and Hrstka, {Ronald F.} and Surendra Dasari",
note = "Funding Information: This publication was made possible by support from the Medical Genome Facility Proteomics Core, Mayo Clinic. The core is a shared resource of the Mayo Clinic Cancer Center (NCI P30 CA15083). We thank Dr. Cristine Charlesworth for her guidance on sample preparation for MS analysis. NPS and SA conceived the study. NPS, SA, SCLH, and RFH contributed to experimental design. Experiments were completed by SA, RFH, SCLH, BA, JPK, BN, and IS. SCLH, RAM, NPS, and SD completed analyses of the bioinformatic and experimental data. RAM and SD developed software for analysis of the proteomics data. SCLH and NPS wrote the manuscript. All co-authors read and approved the submitted version. This work was supported by the National Institutes of Health [NPS: R01 CA211887] and the Mayo Foundation for Medical Education and Research. The authors have no conflicting interests. Funding Information: This publication was made possible by support from the Medical Genome Facility Proteomics Core, Mayo Clinic . The core is a shared resource of the Mayo Clinic Cancer Center (NCI P30 CA15083). We thank Dr. Cristine Charlesworth for her guidance on sample preparation for MS analysis. Funding Information: This work was supported by the National Institutes of Health [NPS: R01 CA211887] and the Mayo Foundation for Medical Education and Research . Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2021",
month = jan,
doi = "10.1016/j.expneurol.2020.113520",
language = "English (US)",
volume = "335",
journal = "Neurodegeneration",
issn = "0014-4886",
publisher = "Academic Press Inc.",
}