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.

Histaminergic transmission slows progression of amyotrophic lateral sclerosis / Apolloni, S.; Amadio, S.; Fabbrizio, P.; Morello, G.; Spampinato, A. G.; Latagliata, E. C.; Salvatori, I.; Proietti, D.; Ferri, A.; Madaro, L.; Puglisi-Allegra, S.; Cavallaro, S.; Volonte, C.. - In: JOURNAL OF CACHEXIA, SARCOPENIA AND MUSCLE. - ISSN 2190-6009. - 10:4(2019), pp. 872-893. [10.1002/jcsm.12422]

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Latagliata E. C.;Salvatori I.;Proietti D.;Madaro L.;Puglisi-Allegra S.;Cavallaro S.;
2019

Abstract

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.
2019
ALS; histamine; microglia; motor neurons; skeletal muscles; SOD1-G93A
01 Pubblicazione su rivista::01a Articolo in rivista
Histaminergic transmission slows progression of amyotrophic lateral sclerosis / Apolloni, S.; Amadio, S.; Fabbrizio, P.; Morello, G.; Spampinato, A. G.; Latagliata, E. C.; Salvatori, I.; Proietti, D.; Ferri, A.; Madaro, L.; Puglisi-Allegra, S.; Cavallaro, S.; Volonte, C.. - In: JOURNAL OF CACHEXIA, SARCOPENIA AND MUSCLE. - ISSN 2190-6009. - 10:4(2019), pp. 872-893. [10.1002/jcsm.12422]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1290577
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