Suppressive effects of 4-phenylbutyrate on the aggregation of Pael receptors and endoplasmic reticulum stress

Kyoko Kubota, Yoshifumi Niinuma, Masayuki Kaneko, Yasunobu Okuma, Mami Sugai, Tomohiro Omura, Mai Uesugi, Takashi Uehara, Toru Hosoi, Yasuyuki Nomura

Research output: Contribution to journalArticlepeer-review

142 Citations (Scopus)


Endoplasmic reticulum (ER) stress is defined as an accumulation of unfolded proteins in the endoplasmic reticulum. 4-phenylbutyrate (4-PBA) has been demonstrated to promote the normal trafficking of the ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) mutant from the ER to the plasma membrane and to restore activity. We have reported that 4-PBA protected against cerebral ischemic injury and ER stress-induced neuronal cell death. In this study, we revealed that 4-PBA possesses chemical chaperone activity in vitro, which prevents the aggregation of denatured α-lactalbumin and bovine serum albumin (BSA). Furthermore, we investigated the effects of 4-PBA on the accumulation of Parkin-associated endothelin receptor-like receptor (Pael-R) pathologically relevant to the loss of dopaminergic neurons in autosomal recessive juvenile parkinsonism (AR-JP). Interestingly, 4-PBA restored the normal expression of Pael-R protein and suppressed ER stress induced by the overexpression of Pael-R. In addition, we showed that 4-PBA attenuated the activation of ER stress-induced signal transduction pathways and subsequent neuronal cell death. Moreover, 4-PBA restored the viability of yeasts that fail to induce an ER stress response under ER stress conditions. These results suggest that 4-PBA suppresses ER stress by directly reducing the amount of misfolded protein, including Pael-R accumulated in the ER.

Original languageEnglish
Pages (from-to)1259-1268
Number of pages10
JournalJournal of Neurochemistry
Issue number5
Publication statusPublished - Jun 2006
Externally publishedYes


  • 4-phenylbutyrate
  • Chemical chaperone
  • Endoplasmic reticulum
  • Endoplasmic reticulum stress
  • Parkinsonism
  • Unfolded protein response

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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