Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Background: Histamine is an immune modulator, neuroprotective, and remyelinating agent, beneficially acting on skeletal muscles and promoting anti-inflammatory features in amyotrophic lateral sclerosis (ALS) microglia. Drugs potentiating the endogenous release of histamine are in trial for neurological diseases, with a role not systematically investigated in ALS. Here, we examine histamine pathway associations in ALS patients and the efficacy of a histamine-mediated therapeutic strategy in ALS mice. Methods: We adopted an integrative multi-omics approach combining gene expression profiles, copy number variants, and single nucleotide polymorphisms of ALS patients. We treated superoxide dismutase 1 (SOD1)-G93A mice that recapitulate key ALS features, with the brain-permeable histamine precursor histidine in the symptomatic phase of the disease and analysed the rescue from disease pathological signs. We examined the action of histamine in cultured SOD1-G93A motor neuron-like cells. Results: We identified 13 histamine-related genes deregulated in the spinal cord of two ALS patient subgroups, among which genes involved in histamine metabolism, receptors, transport, and secretion. Some histamine-related genes overlapped with genomic regions disrupted by DNA copy number and with ALS-linked pathogenic variants. Histidine treatment in SOD1-G93A mice proved broad efficacy in ameliorating ALS features, among which most importantly lifespan, motor performance, microgliosis, muscle atrophy, and motor neurons survival in vivo and in vitro. Conclusions: Our gene set/pathway enrichment analyses and preclinical studies started at the onset of symptoms establish that histamine-related genes are modifiers in ALS, supporting their role as candidate biomarkers and therapeutic targets. We disclose a novel important role for histamine in the characterization of the multi-gene network responsible for ALS and, furthermore, in the drug development process.