A multi-region transcriptomic framework reveals global and region-specific ubiquitin-proteasome system biomarkers in...

The involvement of ubiquitin-proteasome system (UPS) impairment in Alzheimer's disease (AD) is increasing gradually yet the molecular organization of the system throughout the AD brain is poorly understood, as is the distribution of molecular markers. To systemically identify UPS-associated molecular signatures, we carried out a multi-region transcriptomic analysis of six different brain regions in AD patients and age-matched controls. The molecular perturbation of regions recapitulated the known regional vulnerability hierarchy with significant changes observed in the entorhinal cortex and hippocampus as well as middle temporal gyrus and posterior cingulate. A synchronized downregulation of UPS components was observed in the vulnerable regions indicating towards the extensive dysfunction of ubiquitin-mediated protein surveillance and proteasomal degradation. The consistent features associated with UPS disruption were linked with synaptic dysfunction, mitochondrial impairment and loss of proteostatic homeostasis as revealed by the functional analyses. We formulated a framework based on composite prioritization which combined several aspects like differential expression, network topology, regional consistency and diagnostic performance for the purpose of identifying strong biomarker candidates. The analysis revealed the most eminent global biomarkers of AD associated with UPS, namely, PSMB4, SNCA, PSMB7, PSMD1, and UBE3A. UBE2R1 (CDC34) was used to define region-specific biomarker signatures in the entorhinal cortex, UBC in the hippocampus, PSMA3 in middle temporal gyrus, PSMD4 in posterior cingulate cortex and UBE2V2 in superior frontal gyrus. These exploratory results provide the first systems-level biomarker atlas of UPS dysfunction in distinct AD brain regions and suggest that there are potential global and region-specific UPS signatures that could be used in diagnostics and drug development.