Natural Killer Cell Dysregulation During ALS Disease Progression: A Gene Expression Analysis.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative motor neuron disease with a pathophysiology that features dysregulated natural killer (NK) cells that are capable of damaging neurons. Although NK cells are associated with ALS progression and survival, their specific characteristics and how these characteristics change over the course of disease is unknown. The current study examines NK cell gene expression during ALS with the goal of identifying dysregulated genes and pathways in NK cells over the course of disease in order to identify potential new therapeutic targets. ALS participants with an El Escorial ALS diagnosis were recruited from the University of Michigan Pranger ALS Clinic, and control participants were recruited via internet-based notifications. Blood was collected from participants and NK cells were isolated from participants with ALS at two timepoints (baseline and longitudinal) and age- and sex-matched healthy controls at one timepoint. RNA was extracted from the NK cells and quantified using a transcript-counting technology for 578 immune-related genes. Differential gene expression analysis was used to identify individual genes that were dysregulated in ALS at baseline and longitudinally, While GO and KEGG pathway analyses were performed to identify dysregulated pathways at both timepoints. NK cells from participants with ALS (n=36, median age 62.6 years (54.5-69.4), 50% female) showed a 2-fold or greater reduced expression of four pro-inflammatory genes at baseline relative to control participants (N=35, median age 64.3 years (55.2-71.8), 51% female) including IFNG, FCGR1A/B, and FAS; in ALS participants over 130 genes showed a 2-fold change in expression. Dysregulated genes and pathways at the later timepoint were related to cell polarization, activation, signaling, and cell-cell adhesion. In particular, genes associated with classical Type 1 inflammation decreased while Type 2 genes increased. NK cells grow more dysregulated with ALS progression, shifting from a classical Type 1 phenotype to a Type 2 phenotype, though a larger study will be needed to confirm these initial findings. The findings also suggest NK cells contribute to early, but not late, ALS progression. Targeting specific NK cell pathways during early ALS may be a viable therapeutic strategy.