{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:46:34Z","timestamp":1760060794910,"version":"build-2065373602"},"reference-count":31,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of General Medical Sciences of the National Institutes of Health","award":["R25GM058268"],"award-info":[{"award-number":["R25GM058268"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease, marked by considerable clinical and molecular heterogeneity. While several genetic drivers have been linked to familial ALS (fALS), the biology of sporadic ALS (sALS)\u2014which accounts for the majority of ALS cases\u2014remains poorly defined. To address this gap, we analyzed 247 bulk mRNA-sequenced post-mortem tissue samples from the lumbar spinal cord and motor cortex and compared expression profiles between fALS, sALS, and controls. Variance-stabilized DEGs from DESeq2 analysis were used as inputs for weighted gene co-expression network analysis (WGCNA). Finally, gene ontology was used to identify transcriptomic signatures and biological pathways unique to sALS and fALS. In the spinal cord, sALS samples exhibited specific downregulation of mitochondrial complex I subunits (e.g., NDUFS8 and NDUFB7) and regulatory genes (e.g., AURKAIP1 and ATP5F1D), suggesting compromised metabolic resilience. In the motor cortex, a co-expression module associated with adaptive immune function and leukocyte infiltration was downregulated in sALS yet upregulated in fALS, indicating distinct inflammatory pathways between these two forms of ALS. Together, our findings highlight that while sALS and fALS are largely the same disease, they exhibit distinct transcriptomic signatures. By accounting for mode of inheritance in study designs\u2014particularly sALS, which represents ~90% of ALS cases\u2014researchers may reveal deeper insights into ALS pathology. This perspective could enable more targeted therapeutic strategies, ultimately improving outcomes for all ALS patients.<\/jats:p>","DOI":"10.3390\/ijms26189234","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T13:04:44Z","timestamp":1758546284000},"page":"9234","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Stratifying ALS Patients by Mode of Inheritance Reveals Transcriptomic Signatures Specific to sALS and fALS"],"prefix":"10.3390","volume":"26","author":[{"given":"Alexandria","family":"Awai","sequence":"first","affiliation":[{"name":"Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erica L.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiandong","family":"Leng","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Patrickson","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael C.","family":"Zody","sequence":"additional","affiliation":[{"name":"New York Genome Center, New York, NY 10013, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"James W.","family":"Lillard","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"on behalf of the NYGC ALS Consortium","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17085","DOI":"10.1038\/nrdp.2017.85","article-title":"Amyotrophic lateral sclerosis","volume":"3","author":"Hardiman","year":"2017","journal-title":"Nat. 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