ArticleResearch square2025
Adaptive Suppression of MAPT Transcription Maintains Tau Proteostasis in Developing Human Neurons.
Article in Research square, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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8 authors.
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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.
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