# Adaptive Suppression of MAPT Transcription Maintains Tau Proteostasis in Developing Human Neurons

## TL;DR

Human neurons reduce tau production when protein clearance is impaired, helping prevent toxicity and offering new targets for treating tau-related diseases.

## Contribution

The study identifies a transcriptional mechanism that reduces MAPT expression during proteostatic stress in human neurons.

## Key findings

- Proteasome inhibition triggers a proteostasis response and downregulates MAPT transcripts in human neurons.
- Tau protein levels decrease in both proteasome and autophagy-impaired neurons, but only proteasome inhibition reduces MAPT transcripts.
- Transcription factors like E2F1, EVT1, Lhx1, and TCF3 are implicated in regulating MAPT during proteostatic stress.

## Abstract

Developing human neurons express abundant tau yet show little toxicity, suggesting built-in mechanisms that restrain tau when protein clearance falters. We combined human tissue analyses with cell-based perturbation assays to define this response. In iPSC-derived forebrain neurons, brief proteasome blockade with epoxomicin (0.25 μM, 24 h; n=3/condition) triggered a coordinated transcriptomic program: hierarchical clustering of RNA-seq data resolved two opposing modules—an up-regulated proteostasis module (ubiquitin-proteasome, autophagy-lysosome, chaperone-mediated folding) and a down-regulated MAPT-linked neuronal/energetic module (microtubule/organization/transport, synaptic signaling, oxidative phosphorylation). MAPT transcripts decreased by both PCR and RNA sequencing in proteasome but not-autophagy impaired neurons even though tau protein levels decreased in both. Expressing tau from a constitutive promoter bypassed this transcriptional brake and increased tau during proteasome inhibition. Qualitative confocal imaging of human cortex (fetal, adult control, and Alzheimer’s disease) showed tau locally nested within proteasome-positive regions with partial overlap with lysosomes, consistent with increased quality-control engagement when tau burden is high. To nominate regulators coupling proteostatic stress to MAPT repression, we integrated promoter motif enrichment (HOMER), transcription-factor enrichment from curated libraries (ChEA3; MeanRank on up/downregulated sets), and JASPAR scanning of the MAPT promoter. A consensus highlighted E2F1, EVT1, Lhx1, and TCF3 among top candidates for MAPT regulation. Together, these data support a proteostasis-first adaption in which neurons activate quality-control programs while transcriptionally reducing MAPT and allied neuronal demands, offering transcription-factor targets and a framework for modulating tau homeostasis relevant to Alzheimer’s disease and related tauopathies.