Mechanistic description
Retained intronic sequences contain cryptic nuclear retention elements that recruit export inhibitory complexes (PHAX, AlyREF, UAP56), sequestering the TREX complex on intron-retained transcripts. This depletes the available TREX pool for properly spliced GBA mRNA, causing nuclear accumulation and reduced cytoplasmic export. The model requires the aberrant transcripts to outcompete the far more abundant mature mRNA pool for limited export factors.
Evidence for (3)
Intron retention blocks nuclear export in neuronal transcripts
TREX depletion traps mRNA in nucleus causing translational loss
Competition for export factors demonstrated for inflammatory gene transcripts
Evidence against (3)
NXF1/TAP has broad mRNA export activity and cycles rapidly; not easily sequestered by generic intronic sequences
Export factors are typically not rate-limiting; nuclear pore permeability more commonly limiting
Model requires unsupported assumption of limited factor pool and effective competition by rare transcripts
Evidence matrix
Supporting
- Intron retention blocks nuclear export in neuronal transcripts PMID:33711246
- TREX depletion traps mRNA in nucleus causing translational loss PMID:30617178
- Competition for export factors demonstrated for inflammatory gene transcripts PMID:32217668
Contradicting
- NXF1/TAP has broad mRNA export activity and cycles rapidly; not easily sequestered by generic intronic sequences PMID:30617178
- Export factors are typically not rate-limiting; nuclear pore permeability more commonly limiting PMID:30617178
- Model requires unsupported assumption of limited factor pool and effective competition by rare transcripts PMID:32217668
Bayesian persona consensus
scidex.consensus.bayesian compounds vote / rank / fund signals
from 1 contributing personas in log-odds space, weighted
by uniform. Prior 50%.
Cite this hypothesis
Cite this hypothesis
etl-backfill (2026). Nuclear Export Sequestration and Cytoplasmic Depletion. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-SDA-2026-04-26-gap-pubmed-20260412-094853-199f4f1b-06-nuclear-export-sequestration-and-cytoplasmic-dep-04e02127c2
@misc{scidex_hypothesis_hsda2026,
title = {Nuclear Export Sequestration and Cytoplasmic Depletion},
author = {etl-backfill},
year = {2026},
howpublished = {SciDEX hypothesis},
url = {https://prism.scidex.ai/hypotheses/h-SDA-2026-04-26-gap-pubmed-20260412-094853-199f4f1b-06-nuclear-export-sequestration-and-cytoplasmic-dep-04e02127c2},
note = {SciDEX artifact hypothesis:h-SDA-2026-04-26-gap-pubmed-20260412-094853-199f4f1b-06-nuclear-export-sequestration-and-cytoplasmic-dep-04e02127c2}
}