# SOD1 at the Crossroads: Co-Overexpression of Canonical Antioxidant Response and Noncanonical Hydrogen Sulfide Generation Pathways in Down Syndrome, With Immune Cell Implications

## TL;DR

This study explores how Down Syndrome affects immune cells through SOD1 overexpression and links it to oxidative stress and hydrogen sulfide production.

## Contribution

The study reveals a novel connection between SOD1 overexpression and noncanonical hydrogen sulfide generation in Down Syndrome immune dysfunction.

## Key findings

- SOD1 mRNA overexpression is strongly linked to inflammatory conditions in Down Syndrome.
- SOD1 co-overexpression correlates with altered immune cell profiles and elevated inflammatory markers.
- Hydrogen sulfide overproduction in Down Syndrome may occur via thioredoxin-dependent pathways, not CBS.

## Abstract

Accelerated immune cell aging is well-recognized feature of Down Syndrome (DS), a condition caused by trisomy of human chromosome 21 (Hsa21). DS predisposes individuals to recurrent infections, autoimmunity, low bone mass and leukemia. To investigate potential connections between immune cell dysfunction or disruption in DS, serum transcriptomic and proteomic datasets from DS and euploid individuals were examined. High DS superoxide dismutase 1 (SOD1) mRNA expression was consistently found and was strongly associated with an increased odds of inflammatory co-occurring conditions such as pharyngitis. SOD1 mRNA overexpression was also associated with decreased M2-polarized macrophages, increased resting-memory CD4+ T cells, elevated serum interleukin-16 levels and interferon-γ protein levels, indicative of pathological pro-inflammatory immune dysregulation. SOD1 mRNA was co-overexpressed with glutathione and thioredoxin-dependent pathways, both are integral to the antioxidative responses and the generation of hydrogen sulfide (H2S). Although H2S overproduction in DS has been attributed to the overexpression of cystathionine-β-synthase (CBS), no consistent CBS mRNA elevation was observed in this study. Conversely, the increased expression of a thioredoxin-dependent cysteine catabolism pathway suggests noncanonical H2S overproduction in DS distinct from CBS. Our findings highlight the unexpected relationship between oxidative stress homeostasis and H2S overproduction in DS, extending beyond Hsa21 trisomy.