Traumatic brain injury induces cell-type-specific remodelling of the proteostasis network

Abstract Traumatic brain injury (TBI) triggers competing damage and repair processes that can result in chronic neurodegenerative protein conformational disorders. Acute alterations in proteostasis have been reported after injury, but a comprehensive understanding of changes to the proteostasis network (PN) has been limited by the complex cellular pathology of TBI. The recent enumeration of the human PN and advances in single-cell transcriptomics make it possible to delineate PN dynamics in multifactorial diseases such as TBI. Here, we leverage archival mouse and human transcriptomic data to identify cell-type-specific Sub-PNs in the brain and their alteration by TBI. We find characteristic PN gene expression profiles in many cell types and subtypes, reflecting tremendous diversity in the enrichment of specific PN processes. TBI induces a broad transcriptional remodelling of translation, the ubiquitin–proteasome system and nuclear proteostasis machinery across cell types. In addition to this shared response, numerous cell-type-specific responses occur, some of which are conserved between mouse and human, despite differences in injury mechanism and timing. Our extensive characterization of the PN transcriptome across cell type and disease reveals potentially modifiable mechanisms of PN alteration in TBI. More broadly, our results provide a framework for elucidating changes to the PN in complex diseases. This article is part of the Theo Murphy meeting issue ‘ProteostaSys: a systems view of proteostasis’.