A HaloTag–4R-Tau Pulse-Chase Sensor Reveals Neddylation Inhibition Promotes Degradation of Tau in iNeurons
Year: 2026
Type: preprint
Abstract: Tau accumulation is a central driver of neurodegenerative diseases, yet strategies to promote its clearance remain limited. We developed a HaloTag-4R-Tau sensor in human iPSC-derived neurons (iNeurons) that enables sensitive monitoring the kinetics of both lysosomal partitioning and overall cellular turnover of tau. Using this sensor, we screened a small collection of small-molecule modulators of proteostasis network function and identified Neddylation inhibition by Pevonedistat as a robust promoter of soluble tau degradation. Mechanistic analysis including proteomic profiling revealed that Neddylation inhibition hastens HaloTag-Tau clearance via compensatory activation of a proteasome-dependent pathway(s) as well as the autophagy-lysosome pathway. Our findings establish a powerful tool for probing tau homeostasis and highlight Neddylation inhibition as a potential therapeutic approach for enhancing both proteasome and lysosome-mediated tau clearance in tauopathies.
Authors: Qiang Xiao, Zi Gao, Seth Allen, Danny Garza, Richard I. Morimoto, Jeffery W. Kelly
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W7126176038