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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.

SUBMITTER: Hrstka SCL

PROVIDER: S-EPMC7750199 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Tau aggregation within neurons is a critical feature of Alzheimer's disease (AD) and related tauopathies. It is believed that soluble pathologic tau species seed the formation of tau aggregates in a prion-like manner and propagate through connected neurons during the progression of disease. Both soluble and aggregated forms of tau are thought to have neurotoxic properties. In addition, different strains of misfolded tau may cause differential neurotoxicity. In this work, we present an accelerated human neuronal model of tau-induced neurotoxicity that incorporates both soluble tau species and tau aggregation. Using patient-derived induced pluripotent stem cell (iPSC) neurons expressing a tau aggregation biosensor, we develop a cell culture system that allows continuous assessment of both induced tau aggregation and neuronal viability at single-cell resolution for periods of >1 week. We show that exogenous tau "seed" uptake, as measured by tau repeat domain (TauRD) reporter aggregation, increases the risk for subsequent neuronal death in vitro These results are the first to directly visualize neuronal TauRD aggregation and subsequent cell death in single human iPSC neurons. Specific morphologic strains or patterns of TauRD aggregation are then identified and associated with differing neurotoxicity. Furthermore, we demonstrate that familial AD iPSC neurons expressing the PSEN1 L435F mutation exhibit accelerated TauRD aggregation kinetics and a tau strain propagation bias when compared with control iPSC neurons.SIGNIFICANCE STATEMENT Neuronal intracellular aggregation of the microtubule binding protein tau occurs in Alzheimer's disease and related neurodegenerative tauopathies. Tau aggregates are believed to spread from neuron to neuron via prion-like misfolded tau seeds. Our work develops a human neuronal live-imaging system to visualize seeded tau aggregation and tau-induced neurotoxicity within single neurons. Using an aggregation-sensing tau reporter, we find that neuronal uptake and propagation of tau seeds reduces subsequent survival. In addition, human induced pluripotent stem cell (iPSC) neurons carrying an Alzheimer's disease-causing mutation in presenilin-1 undergo tau seeding more rapidly than control iPSC neurons. However, they do not show subsequent differences in neuronal survival. Finally, specific morphologies of tau aggregates are associated with increased neurotoxicity.

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Proteomic analysis of human iPSC-derived sensory neurons implicates cell stress and microtubule dynamics dysfunction in bortezomib-induced peripheral neurotoxicity.

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