title: Paeoniflorin eliminates a mutant AR via NF-YA-dependent proteolysis in spinal and bulbar muscular atrophy.
abstract: The accumulation of abnormal proteins is a common characteristic of neurodegenerative diseases. This accumulation reflects a severe disturbance of cellular homeostasis in pathogenic protein clearance. Here, we demonstrated that the activation of the two major proteolytic machineries, the molecular chaperone-ubiquitin proteasome system (UPS) and the autophagy system, were simultaneously enhanced by paeoniflorin (PF), a major component of Paeonia plants, and exerted therapeutic effects in models of spinal and bulbar muscular atrophy (SBMA). PF significantly increased the expression of nuclear factor-YA (NF-YA), which strongly upregulated the molecules involved in the proteolytic machinery [molecular chaperones, carboxyl terminus of Hsc70-interacting protein and transcription factor EB], which thus mitigated the behavioral and pathological impairments in an SBMA mouse model through the upregulation of pathogenic androgen receptor protein clearance in motor neurons and muscles. These findings demonstrated that PF is able to enhance both the UPS and autophagy systems by upregulating the expression of NF-YA, which promotes therapeutic effects in an SBMA model.
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Genki
authors.initials: G
authors.lastname: Tohnai
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan hadachi-ns@umin.org sobueg@med.nagoya-u.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Adachi
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Doi
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Naohide
authors.initials: N
authors.lastname: Kondo
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Iida
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakatsuji
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Qiang
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Speech Pathology and Audiology, Aichi-Gakuin University School of Health Science, 12 Araike, Iwasaki-cho, Nisshin 470-0195, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Cell and Stress Biology, Department of Environmental Biology, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Ohtsuka
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan hadachi-ns@umin.org sobueg@med.nagoya-u.ac.jp.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000502:physiology / Q000528:radiation effects; D005960:Glucosides / Q000627:therapeutic use*; D007150:Immunohistochemistry; D051379:Mice; D039821:Monoterpenes / Q000627:therapeutic use*; D009134:Muscular Atrophy, Spinal; D059748:Proteolysis / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics*; D006027:Glycosides
chemical_list: D005960:Glucosides; D039821:Monoterpenes; D011944:Receptors, Androgen; C410798:AR protein, human; C015423:peoniflorin; D006027:Glycosides