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

Abstract

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 DF508 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 a-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.

A chemical chaperone 4-PBA ameliorates palmitate-induced inhibition of glucose-stimulated insulin secretion (GSIS)

“…Chemical chaperones, such as glycerol, dimethylsulfoxide (DMSO) and 4-PBA, have been used to improve the misfolding and mislocalization of proteins and to reduce ER stress-mediated cellular dysfunction [37]. In particular, 4-PBA was reported to facilitate the correct folding of misfolded and unfolded protein in vivo as well as in vitro [38]. Recently, 4-PBA was reported to be capable of alleviating ER stress and causing the normalization of hyperglycemia in obese and diabetic mice by improving insulin sensitivity [16].…”

Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury

“…PBA has multiple biological activities, including as HDAC inhibition [28], chemical chaperoning upon endoplasmic reticulum (ER) stress [38,39], ammonia scavenging in urea cycle dysfunction [31,32]. Urea cycle dysfunction in heart has never been reported after decades of intensive research of ADR cardiotoxicity.…”

Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer's Disease Mouse Model

“…ER stress activates GSK3b through dephosphorylation of Ser9 (Song et al, 2002). 4-PBA has been shown to act as a chemical chaperone reversing the mislocalization and/ or aggregation of proteins associated with human diseases (Rubenstein and Zeitlin, 2000;Kubota et al, 2006). It has been described that valproate, another chemical chaperone, protects cells from ER stress, at least in part by inhibiting GSK3b (Kim et al, 2005).…”