Meta-Analysis of Gene Expression in Bulk-Processed Post-Mortem Spinal Cord from ALS Patients and Normal Controls

TL;DR

This study identifies gene expression changes in spinal cord tissue from ALS patients, highlighting immune and myelin-related processes in disease progression.

Contribution

A meta-analysis of spinal cord gene expression reveals distinct immune and oligodendrocyte-related gene patterns in ALS.

Findings

213 differentially expressed genes were identified, with immune-related genes increased and myelin-related genes decreased in ALS.

ALS-increased genes were strongly expressed by microglia and linked to immune response and MHC class II.

ALS-decreased genes were associated with mature oligodendrocytes and myelin production, with expression strongest in spinal white matter.

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron failure and poor prognosis. This study performed a meta-analysis of gene expression datasets that compared bulk-processed post-mortem spinal cord from ALS and control (CTL) patients. The analysis included 569 samples (454 ALS, 115 CTL) from 348 individuals (262 ALS, 86 CTL). Patterns of differential expression bias, related to mRNA abundance, gene length and GC content, were discernable from individual studies but attenuated by meta-analysis. A total of 213 differentially expressed genes (DEGs) were identified (144 ALS-increased, 69 ALS-decreased). ALS-increased DEGs were most highly expressed by microglia and associated with MHC class II, immune response and leukocyte activation. ALS-decreased DEGs were abundantly expressed by mature oligodendrocytes (e.g., the MOL5 phenotype) and associated with myelin production, plasma membrane and sterol metabolism. Comparison to spatial transcriptomics data showed that DEGs were prominently expressed in white matter, with increased DEG expression strongest in the ventral/lateral white matter. These results highlight white matter as the spinal cord region most strongly associated with the shifts in mRNA abundance observed in bulk-processed tissues. These shifts can be explained by attrition of mature oligodendrocytes and an ALS-emergent microglia phenotype that is partly shared among neurodegenerative conditions.

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