Characterization of Gene Expression Phenotype in Amyotrophic Lateral Sclerosis Monocytes

Abstract

IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a common adult-onset neurodegenerative disease characterized by selective loss of upper and lower motor neurons. Patients with ALS have persistent peripheral and central inflammatory responses including abnormally functioning T cells and activated microglia. However, much less is known about the inflammatory gene profile of circulating innate immune monocytes in these patients.OBJECTIVE To characterize the transcriptomics of peripheral monocytes in patients with ALS. DESIGN, SETTING, AND PARTICIPANTS Monocytes were isolated from peripheral blood of 43 patients with ALS and 22 healthy control individuals. Total RNA was extracted from the monocytes and subjected to deep RNA sequencing, and these results were validated by quantitative reverse transcription polymerase chain reaction. MAIN OUTCOMES AND MEASURESThe differential expressed gene signatures of these monocytes were identified using unbiased RNA sequencing strategy for gene expression profiling. RESULTSThe demographics between the patients with ALS (mean [SD] age, 58.8 [1.57] years; 55.8% were men and 44.2% were women; 90.7% were white, 4.65% were Hispanic, 2.33% were black, and 2.33% were Asian) and control individuals were similar (mean [SD] age, 57.6 [2.15] years; 50.0% were men and 50.0% were women; 90.9% were white, none were Hispanic, none were black, and 9.09% were Asian). RNA sequencing data from negative selected monocytes revealed 233 differential expressed genes in ALS monocytes compared with healthy control monocytes. Notably, ALS monocytes demonstrated a unique inflammation-related gene expression profile, the most prominent of which, including IL1B, IL8, FOSB, CXCL1, and CXCL2, were confirmed by quantitative reverse transcription polymerase chain reaction (IL8, mean [SE], 1.

Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial

“…Additional disease mechanisms offer another explanation for relative lack of efficacy in "Fast Progressor" patients, with targeted therapies expected to work on only a subset of ALS patients. Indeed, gene expression profiling and proteomic studies in ALS have successfully differentiated patients with rapid and non-rapid progressive disease (the latter defined as having an equivalent DFS of around 1.0 point/month) (19,(28)(29)(30)(31), such evidence supporting the premise that these groups represent pathophysiologically distinct forms of ALS.…”

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

“…Another study reported increased production of neurotoxic cytokines by monocytes from twins with ALS compared to the unaffected twin (108). Increased peripheral monocyte expression of inflammatory genes correlates with disease progression (69). Another study reported expression of activation markers on monocytes but reduced expression of HLA-DR (57).…”

High neutrophil-to-lymphocyte ratio predicts short survival duration in amyotrophic lateral sclerosis

“…Motor neuron degeneration in ALS occurs both cell-autonomously within motor neurons and non-cell-autonomously involving non-neuronal cells such as astrocytes and microglia 4,5 . Interestingly, alterations in peripheral immune cells as well as glial cells in the central nervous system (CNS) have been reported in humans and mouse models of ALS [6][7][8][9][10][11] . Leukocyte alterations in easily accessible peripheral blood may therefore be useful disease biomarkers.…”