Batch- and Composition-Controlled Reanalysis of Bulk and Single-Nucleus Transcriptomes Reveals Co-Enrichment of Glial Complement and of Translational Signatures in Parkinson’s Disease and Amyotrophic Lateral Sclerosis

Failure of axonal maintenance is proposed as a mechanism shared by Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). We reanalysed three public post-mortem resources under one rule set: bulk RNA-seq of 1242 samples from 319 donors (GSE153960) and midbrain single-nucleus RNA-seq (GSE157783, GSE178265). As a contributing project, a second batch variable tracked diagnosis in both cord segments and was completely separated from it in three cortical regions, which we removed. Adjusting for this removed a third of the naive differential expression. In ALS cord, the dominant depleted program was microtubule-based axonal transport (normalised enrichment score −2.40, FDR < 0.001); a regeneration-associated panel reached significance in none of ten fits. An ALS cord signature carried into the PD midbrain and scored highest on microglia in all 11 donors (+3.55 versus +0.73 next). Of 86 gene sets significant in both diseases, a translation block contained the GCN2 amino-acid-deficiency response. Both axes are compartment-level: within PD microglia, the complement panel is null (+0.21, p = 0.57). No GCN2 activity was measured, and the ALS cord is compared against PD midbrain. The axes that survive this control are glial and translational; the axonal question is not adjudicable in PD, where the panel score tracks dopaminergic content.