Multi-regional transcriptomic profiling reveals divergent molecular mechanisms in ALS-related neurodegeneration

Neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) remain largely unsolved, with complex etiology yet to be fully elucidated. The most common genetic cause of ALS in both familial and sporadic cases is the expansion of a hexanucleotide repeat in the C9orf72 gene. To systematically dissect the molecular landscape of ALS, we performed integrative transcriptomic analyses across multiple central nervous system regions from ALS patients carrying pathological C9orf72 repeat expansions (ALS-C9) and those without the mutation (ALS-non-C9). In parallel, we performed transcriptome-wide cell-type deconvolution to assess the cellular composition of neuronal and non-neuronal populations. We identified a set of dysregulated molecular pathways that were consistently altered in both ALS-C9 and ALS-non-C9 patients, suggesting shared pathogenic mechanisms. Distinct gene-specific alterations also pointed to divergent subtype-dependent molecular trajectories. Gene-specific alterations were also associated with short clinical duration in ALS-non-C9, highlighting a sex-dependent immunological contribution to disease outcome. Our cross-regional integrative transcriptomic analyses reveal both convergent and divergent molecular and cellular features between ALS-C9 and ALS-non-C9 subgroups, underscoring the clinical heterogeneity of ALS and providing a framework for subtype- and sex-specific therapeutic stratifications.