title: Naratriptan mitigates CGRP1-associated motor neuron degeneration caused by an expanded polyglutamine repeat tract.
abstract: Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by the expansion of the CAG triplet repeat within the androgen receptor (AR) gene. Here, we demonstrated that pathogenic AR upregulates the gene encoding calcitonin gene-related peptide α (CGRP1). In neuronal cells, overexpression of CGRP1 induced cellular damage via the activation of the c-Jun N-terminal kinase (JNK) pathway, whereas pharmacological suppression of CGRP1 or JNK attenuated the neurotoxic effects of pathogenic AR. The depletion of CGRP1 inactivated JNK and suppressed neurodegeneration in a mouse model of SBMA. Naratriptan, a serotonin 1B/1D (5-hydroxytryptamine 1B/1D, or 5-HT1B/1D) receptor agonist, decreased CGRP1 expression via the induction of dual-specificity protein phosphatase 1 (DUSP1), attenuated JNK activity and mitigated pathogenic AR-mediated neuronal damage in cellular and mouse SBMA models. These observations suggest that pharmacological activation of the 5-HT1B/1D receptor may be used therapeutically to treat SBMA and other polyglutamine-related neurodegenerative diseases.
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Minamiyama
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Adachi
authors.forename: Hideki
authors.initials: H
authors.lastname: Doi
authors.forename: Naohide
authors.initials: N
authors.lastname: Kondo
authors.forename: Madoka
authors.initials: M
authors.lastname: Iida
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ishigaki
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Fujioka
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Yu
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
mesh_terms: D000818:Animals; D002116:Calcitonin / Q000235:genetics / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide; D002470:Cell Survival; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000235:genetics; D020966:Muscular Disorders, Atrophic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010455:Peptides; D010880:Piperidines / Q000494:pharmacology*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D019680:Trinucleotide Repeat Expansion; D014363:Tryptamines / Q000494:pharmacology*
chemical_list: C000606590:Calca protein, mouse; D010455:Peptides; D010880:Piperidines; D011498:Protein Precursors; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D058825:Serotonin 5-HT1 Receptor Agonists; D014363:Tryptamines; C097188:polyglutamine; D002116:Calcitonin; D048031:JNK Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D015740:Calcitonin Gene-Related Peptide; C106783:naratriptan