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

被引:153
作者
Kubota, Kyoko
Niinuma, Yoshifumi
Kaneko, Masayuki
Okuma, Yasunobu
Sugai, Mami
Omura, Tomohiro
Uesugi, Mai
Uehara, Takashi
Hosoi, Toru
Nomura, Yasuyuki [1 ]
机构
[1] Daiichi Univ, Coll Pharmaceut Sci, Fukuoka 8158511, Japan
[2] Hokkaido Univ, Grad Sch Pharmaceut Sci, Dept Pharmacol, Sapporo, Hokkaido, Japan
[3] Chiba Inst Sci, Fac Pharmaceut Sci, Dept Pharmacol, Choshi, Japan
[4] Hiroshima Univ, Grad Sch Biomed Sci, Dept Pharmacotherapy, Hiroshima, Japan
[5] Daiichi Univ, Coll Pharmaceut Sci, Fukuoka, Japan
[6] Hokkaido Univ, Grad Sch Med, Sapporo, Hokkaido, Japan
关键词
4-phenylbutyrate; chemical chaperone; endoplasmic reticulum; endoplasmic reticulum stress; parkinsonism; unfolded protein response;
D O I
10.1111/j.1471-4159.2006.03782.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Delta F508 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 alpha-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.
引用
收藏
页码:1259 / 1268
页数:10
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