Person-specific differences in ubiquitin-proteasome mediated proteostasis in human neurons

DISCUSSION: These findings reveal that genetic variation influences basal UPS activity in human neurons and differentially sensitizes them to external factors perturbing the UPS, leading to the accumulation of aggregation-prone proteins such as tau.HIGHLIGHTS: Polygenic risk score for AD is associated with the ubiquitin-proteasome system (UPS) in neurons. Basal proteasome activity correlates with aggregation-prone protein levels in neurons. Genetic variation affects the response to proteasome inhibition in neurons. Neuronal proteasome perturbation induces an elevation in specific proteins involved in proteostasis. Low basal proteasome activity leads to enhanced tau accumulation with UPS challenge.PMID:38470006 | DOI:10.1002/alz.13680

Source: The Journal of Alzheimers Association - March 12, 2024 Category: Psychiatry Authors: Yi-Chen Hsieh Zachary M Augur Mason Arbery Nancy Ashour Katharine Barrett Richard V Pearse Earvin S Tio Duc M Duong Daniel Felsky Philip L De Jager David A Bennett Nicholas T Seyfried Tracy L Young-Pearse Source Type: research