ALS-associated cytoskeletal and glial gene expression: evidence consistent with developmental pathway re-engagement

We examined whether amyotrophic lateral sclerosis (ALS) is associated with cytoskeletal and glial transcriptional patterns compatible with developmental pathway re-engagement, while recognizing that similar patterns may arise from injury responses and altered cell composition.

Postmortem RNA-sequencing data from the Target ALS Postmortem Tissue Core were analyzed using linear mixed-effects models accounting for repeated tissue samples within subjects. Models were adjusted for tissue source, age at death, sex, and postmortem interval. Composite scores represented Arp2/3 activity, SOX9/MEGF10 developmental-glial expression, and MYH10-associated transport imbalance.

ALS was associated with increased Arp2/3 expression (β = 0.399, P = 8.26 × 10^-9), SOX9/MEGF10 expression (β = 0.643, P = 4.28 × 10^-6), MYH10 expression (β = 0.308, P = 0.000801), and MYH10-KIF5C transport mismatch (β = 0.121, P = 0.00537); all remained significant after false-discovery-rate correction. The MYH10-Arp2/3 contractility index was not significant (β = -0.0909, P = 0.107).

ALS was associated with higher expression of selected cytoskeletal and glial genes in bulk postmortem tissue. These cross-sectional associations are compatible with, but do not demonstrate, developmental program reactivation, altered protein activity, or causation. Cell-resolved and functional studies are needed.