{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T04:59:25Z","timestamp":1792213165400,"version":"4.4.0"},"reference-count":168,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T00:00:00Z","timestamp":1713225600000},"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. Genet."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>ALS is a fatal neurodegenerative disease for which underlying mechanisms are incompletely understood. The motor neuron is a central player in ALS pathogenesis but different transcriptome signatures have been derived from bulk analysis of post-mortem tissue and iPSC-derived motor neurons (iPSC-MNs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study performed a meta-analysis of six gene expression studies (microarray and RNA-seq) in which laser capture microdissection (LCM) was used to isolate lower motor neurons from post-mortem spinal cords of ALS and control (CTL) subjects. Differentially expressed genes (DEGs) with consistent ALS <jats:italic>versus<\/jats:italic> CTL expression differences across studies were identified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The analysis identified 222 ALS-increased DEGs (FDR &amp;lt;0.10, SMD &amp;gt;0.80) and 278 ALS-decreased DEGs (FDR &amp;lt;0.10, SMD &amp;lt; \u22120.80). ALS-increased DEGs were linked to PI3K-AKT signaling, innate immunity, inflammation, motor neuron differentiation and extracellular matrix. ALS-decreased DEGs were associated with the ubiquitin-proteosome system, microtubules, axon growth, RNA-binding proteins and synaptic membrane. ALS-decreased DEG mRNAs frequently interacted with RNA-binding proteins (e.g., FUS, HuR). The complete set of DEGs (increased and decreased) overlapped significantly with genes near ALS-associated SNP loci (<jats:italic>p<\/jats:italic> &amp;lt; 0.01). Transcription factor target motifs with increased proximity to ALS-increased DEGs were identified, most notably DNA elements predicted to interact with forkhead transcription factors (e.g., FOXP1) and motor neuron and pancreas homeobox 1 (MNX1). Some of these DNA elements overlie ALS-associated SNPs within known enhancers and are predicted to have genotype-dependent MNX1 interactions. DEGs were compared to those identified from SOD1-G93A mice and bulk spinal cord segments or iPSC-MNs from ALS patients. There was good correspondence with transcriptome changes from SOD1-G93A mice (<jats:italic>r<\/jats:italic> \u2264 0.408) but most DEGs were not differentially expressed in bulk spinal cords or iPSC-MNs and transcriptome-wide effect size correlations were weak (bulk tissue: <jats:italic>r<\/jats:italic> \u2264 0.207, iPSC-MN: <jats:italic>r<\/jats:italic> \u2264 0.037).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study defines a robust transcriptome signature from LCM-based motor neuron studies of post-mortem tissue from ALS and CTL subjects. This signature differs from those obtained from analysis of bulk spinal cord segments and iPSC-MNs. Results provide insight into mechanisms underlying gene dysregulation in ALS and highlight connections between these mechanisms, ALS genetics, and motor neuron biology.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2024.1385114","type":"journal-article","created":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T08:22:26Z","timestamp":1713255746000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Meta-analysis of differential gene expression in lower motor neurons isolated by laser capture microdissection from post-mortem ALS spinal cords"],"prefix":"10.3389","volume":"15","author":[{"given":"William R.","family":"Swindell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,4,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6778","DOI":"10.1038\/ncomms7778","article-title":"Foxp1-mediated programming of limb-innervating motor neurons from mouse and human embryonic stem cells","volume":"6","author":"Adams","year":"2015","journal-title":"Nat. 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