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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcitonin / genetics
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Calcitonin / metabolism*
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Calcitonin Gene-Related Peptide
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Cell Survival
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Cells, Cultured
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Dual Specificity Phosphatase 1 / biosynthesis
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / metabolism
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Male
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Mice
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Mice, Transgenic
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Motor Neuron Disease / genetics
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Muscular Disorders, Atrophic / genetics*
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Muscular Disorders, Atrophic / metabolism
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Muscular Disorders, Atrophic / pathology
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Peptides*
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Piperidines / pharmacology*
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Protein Precursors / genetics
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Protein Precursors / metabolism*
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RNA Interference
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RNA, Small Interfering
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Receptors, Androgen / genetics*
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Receptors, Androgen / metabolism
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Serotonin 5-HT1 Receptor Agonists / pharmacology*
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Spinal Cord / metabolism
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Spinal Cord / pathology
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Trinucleotide Repeat Expansion*
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Tryptamines / pharmacology*
Substances
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Calca protein, mouse
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Peptides
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Piperidines
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Protein Precursors
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RNA, Small Interfering
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Receptors, Androgen
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Serotonin 5-HT1 Receptor Agonists
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Tryptamines
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polyglutamine
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Calcitonin
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JNK Mitogen-Activated Protein Kinases
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Dual Specificity Phosphatase 1
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Dusp1 protein, mouse
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Calcitonin Gene-Related Peptide
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naratriptan