Paeoniflorin eliminates a mutant AR via NF-YA-dependent proteolysis in spinal and bulbar muscular atrophy

Genki Tohnai, Hiroaki Adachi, Masahisa Katsuno, Hideki Doi, Shinjiro Matsumoto, Naohide Kondo, Yu Miyazaki, Madoka Iida, Hideaki Nakatsuji, Qiang Qiang, Ying Ding, Hirohisa Watanabe, Masahiko Yamamoto, Kenzo Ohtsuka, Gen Sobue

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19 Citations (Scopus)

Abstract

The accumulation of abnormal proteins is a common characteristic of neurodegenerative diseases. This accumulation reflects a severe disturbance of cellularhomeostasis in pathogenic protein clearance. Here,wedemonstrated 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.

Original languageEnglish
Article numberddu066
Pages (from-to)3552-3565
Number of pages14
JournalHuman molecular genetics
Volume23
Issue number13
DOIs
Publication statusPublished - 07-2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Tohnai, G., Adachi, H., Katsuno, M., Doi, H., Matsumoto, S., Kondo, N., Miyazaki, Y., Iida, M., Nakatsuji, H., Qiang, Q., Ding, Y., Watanabe, H., Yamamoto, M., Ohtsuka, K., & Sobue, G. (2014). Paeoniflorin eliminates a mutant AR via NF-YA-dependent proteolysis in spinal and bulbar muscular atrophy. Human molecular genetics, 23(13), 3552-3565. [ddu066]. https://doi.org/10.1093/hmg/ddu066