title: Aberrant neuregulin 1 signaling in amyotrophic lateral sclerosis.
abstract: Neuregulin 1 (NRG1) is a neuron-derived trophic molecule that supports axoglial and neuromuscular development through several alternatively spliced isoforms; its possible role in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS) is not known. We analyzed the relationship of NRG1 isoform expression to glial cell activation and motor neuron loss in spinal cords of ALS patients and during disease progression in the superoxide dismutase 1 (SOD1) ALS mouse model. Microgliosis, astrocytosis, and motor neuron loss were observed in the ventral horns in ALS patients and were increased in SOD1 mice along with disease progression. Type III (membrane-bound) NRG1 expression was reduced in parallel with motor neuron loss, but Type I (secreted) NRG1 expression was increased and was associated with glial activation. Increased NRG1 receptor activation was observed on activated microglia in both ALS patients and in SOD1 mice. This activation was observed at the time of disease onset and before upregulation of NRG1 gene expression in the mice. The downregulation of membrane-bound Type III NRG1 forms may reflect motor neuron loss, but increased signaling by secreted-type NRG1 isoforms could contribute to disease pathogenesis through glial cell activation. NRG1 might, therefore, represent a novel therapeutic target against disease progression in ALS.
authors.affiliation: Hiller ALS Center and Department of Neurology, Wayne State University, Detroit, Michigan, USA. fsong@med.wayne.edu
authors.forename: Fei
authors.initials: F
authors.lastname: Song
authors.forename: Pohung
authors.initials: P
authors.lastname: Chiang
authors.forename: Jiajing
authors.initials: J
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Ravits
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Loeb
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics; D004185:Disability Evaluation; D004195:Disease Models, Animal; D018450:Disease Progression; D005192:Family Health; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D020890:Neuregulin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D020890:Neuregulin-1; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C094131:NRG1 protein, human; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse