Multiomic ALS signatures highlight sex differences and molecular subclusters and identify the MAPK pathway as therapeutic target

Abstract

AbstractAmyotrophic lateral sclerosis (ALS) is the most common motor neuron disease and lacks effective disease-modifying treatments. Here, we performed a multiomic analysis of the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, as well as four transgenic mouse models of C9orf72-, SOD1-, TDP-43-, and FUS-ALS to characterize early and sex-specific disease mechanisms in ALS. Integrated analyses of transcriptomes, (phospho)proteomes, and miRNAomes revealed more pronounced changes in male patients. We identified transcriptome-based human ALS subclusters driven by the immune response, extracellular matrix, mitochondrial respiration, and RNA metabolism. The molecular signatures of human subclusters were reflected in specific mouse models. Individual and integrative multiomics analyses highlighted the mitogen-activated protein kinase pathway as an early disease-relevant mechanism. Its modulation by trametinib in vitro and in vivo validated that mitogen-activated protein kinase kinase 2 is a promising therapeutic target with beneficial effects in female patients.