A HaloTag-4R-Tau Pulse-Chase Sensor Reveals Neddylation Inhibition Promotes Degradation of Tau in iNeurons

  • bioRxiv. 2026 Jan 29:2026.01.28.702105. doi: 10.64898/2026.01.28.702105.
Qiang Xiao  1  2 ,  Zi Gao  1  2 ,  Seth Allen  1  2 ,  Danny Garza  1  2 ,  Richard I Morimoto  3 ,  Jeffery W Kelly  1  2
Affiliations
  • 1. Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
  • 2. The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037.
  • 3. Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208.
PMID: 41659571 DOI: 10.64898/2026.01.28.702105
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.

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