{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T06:31:28Z","timestamp":1786343488036,"version":"build-2736575974"},"reference-count":7,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>\n                    EIF2S1 (eIF2\u03b1, translation initiation surveillance) and PELO (Pelota, ribosome rescue) operate within established ribosome-associated quality control and translation-initiation surveillance pathways. Direct cross-talk between these systems is mediated through ZAK\/GCN-mediated eIF2\u03b1 phosphorylation under ribosome-stall stress. At the transcriptional layer, however, EIF2S1-PELO co-regulation has not been quantitatively characterized. Using pairing-family architectural decomposition on multi-region GTEx co-expression and BA9 prefrontal cortex RNA-seq from Parkinson\u2019s disease and control donors (GSE68719,\n                    <jats:italic>n<\/jats:italic>\n                    \u202f=\u202f44 controls,\n                    <jats:italic>n<\/jats:italic>\n                    \u202f=\u202f29 PD), we find: (1) EIF2S1 and PELO share near-identical genome-wide co-expression architecture (continuous Weighted Jaccard\u202f=\u202f0.914) with substantial top-partner overlap (binary Jaccard at top 5%\u202f=\u202f0.490), producing a Type 1 dissociation gap of 0.424, significantly smaller than 200 random gene-pair gaps (mean 0.644,\n                    <jats:italic>z<\/jats:italic>\n                    \u202f=\u202f\u22122.57, permutation\n                    <jats:italic>p<\/jats:italic>\n                    \u202f=\u202f0.015), and the lowest gap in a 21-pair quality-control gene panel; (2) the relationship is approximately linear-monotonic (Type 6 Pearson-Spearman gap\u202f\u2248\u202f0.004); (3) cellular functional co-dependency in DepMap CRISPR screens is essentially zero (Jaccard\u202f=\u202f0.006, gene-effect Pearson\n                    <jats:italic>r<\/jats:italic>\n                    \u202f=\u202f\u22120.07), consistent with layer separation between regulatory architecture and cellular phenotype; (4) in an exploratory single-cohort comparison of PD versus control prefrontal cortex, the dissociation gap was larger in PD (0.536 versus 0.424 in control), but this between-group difference did not reach statistical significance under a group-label permutation test (\n                    <jats:italic>p<\/jats:italic>\n                    \u202f=\u202f0.40; bootstrap 95% CI on the difference [\u22120.14, 0.29]), so we present it as a hypothesis for replication rather than an established effect. These findings characterize EIF2S1-PELO transcriptional co-regulation as a constitutive architectural feature distinct from the ZAK\/GCN-mediated direct mechanism. The constitutive coupling replicated in independent Alzheimer\u2019s disease and ALS frontal-cortex cohorts and across microarray and RNA-seq platforms; a disease-associated weakening of the coupling was directionally consistent across all three diseases but did not reach statistical significance. We note that co-expression patterns are consistent with shared upstream regulatory programs but do not by themselves establish direct co-regulation; the architectural findings reported here are correlational at the transcriptional layer.\n                  <\/jats:p>","DOI":"10.3389\/fnmol.2026.1817096","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T06:19:55Z","timestamp":1786342795000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["EIF2S1-PELO co-expression architecture in human brain: pairing-family decomposition reveals constitutive transcriptional coupling and functional layer separation"],"prefix":"10.3389","volume":"19","author":[{"given":"Drake H.","family":"Harbert","sequence":"first","affiliation":[{"name":"Inner Architecture LLC","place":["Canton, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s12920-016-0164-y","article-title":"Integrative analyses of proteomics and RNA transcriptomics implicate mitochondrial processes, protein folding pathways and GWAS loci in Parkinson disease","volume":"9","author":"Dumitriu","year":"2016","journal-title":"BMC Med."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1830847","DOI":"10.3389\/fphar.2026.1830847","article-title":"Sigma-1 and Sigma-2 receptors exhibit divergent genome-wide co-expression architectures in human brain despite shared subcellular localization","volume":"17","author":"Harbert","year":"2026","journal-title":"Front. 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