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ID 47058
file
creator
Mimori, Seisuke
Okuma, Yasunobu
Kawada, Koichi
Nomura, Yasuyuki
Hamana, Hiroshi
subject
4-phenylbutyrate
3-phenylpropionate
endoplasmic reticulum stress
NDC
Medical sciences
abstract
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.
description
This work was partly supported by a Sasakawa Scientific Research Grant from the Japan Science Society. In addition, this work was supported by Grants-in-Aid for Scientific Research (21590101, 21300142, 20659013, and 21590120) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
journal title
Biological and Pharmaceutical Bulletin
volume
Volume 35
issue
Issue 1
start page
84
end page
90
date of issued
2012-10-01
publisher
The Pharmaceutical Society of Japan
issn
0918-6158
1347-5215
ncid
publisher doi
language
eng
nii type
Journal Article
HU type
Journal Articles
DCMI type
text
format
application/pdf
text version
publisher
rights
© 2012 The Pharmaceutical Society of Japan
relation url
department
Graduate School of Biomedical & Health Sciences