Endoplasmic reticulum (ER) stress responses play an important role in
neurodegenerative diseases.
Sodium 4-phenylbutyrate (4-PBA) is a terminal aromatic substituted
fatty acid that has been used for the treatment of
urea cycle disorders.
4-PBA possesses in vitro chemical chaperone activity and reduces the accumulation of Parkin-associated
endothelin receptor-like receptor (Pael-R), which is involved in
autosomal recessive juvenile parkinsonism (AR-JP). In this study, we show that terminal aromatic substituted
fatty acids, including
3-phenylpropionate (3-PPA),
4-PBA,
5-phenylvaleric acid, and 6-phenylhexanoic
acid, prevented the aggregation of
lactalbumin and
bovine serum albumin. Aggregation inhibition increased relative to the number of carbons in the
fatty acids. Moreover, these compounds protected cells against ER stress-induced neuronal cell death. The cytoprotective effect correlated with the in vitro chemical chaperone activity. Similarly, cell viability decreased on treatment with
tunicamycin, an ER stress inducer, and was dependent on the number of carbons in the
fatty acids. Moreover, the expression of
glucose-regulated proteins 94 and 78 (
GRP94, 78) decreased according to the number of carbons in the
fatty acids. Furthermore, we investigated the effects of these compounds on the accumulation of Pael-R in
neuroblastoma cells. 3-PPA and
4-PBA significantly suppressed neuronal cell death caused by ER stress induced by the overexpression of Pael-R. Overexpressed Pael-R accumulated in the ER of cells. With 3-PPA and
4-PBA treatment, the localization of the overexpressed Pael-R shifted away from the ER to the cytoplasmic membrane. These results suggest that terminal aromatic substituted
fatty acids are potential candidates for the treatment of
neurodegenerative diseases.