Naringenin Inhibits the Aggregation of Expanded Polyglutamine Tract-Containing Protein through the Induction of Endoplasmic Reticulum Chaperone GRP78

Polyglutamine (polyQ) diseases are inherited neurodegenerative diseases characterized by the aggregation of proteins containing expanded polyQ tract. Recently, we have shown that GRP78, the endoplasmic reticulum (ER) chaperone, was significantly decreased in the cells expressing enhanced green fluorescent protein with a pathological-length polyQ tract (EGFP-polyQ97), but not with a non-pathological-length polyQ tract (EGFP-polyQ24), and the expression levels of GRP78 were inversely related to the aggregation of EGFP-polyQ97. In this study, we performed the screening for compounds that modulate the GRP78 expression in herbal medicines, and found that naringenin, one of the major constitutions of Kanzo (Glycyrrhizae Radix), induced the expression of GRP78 in several mammalian cells. Furthermore, naringenin suppressed the protein aggregation caused by EGFP-polyQ97 in mammalian cells. These findings suggested that naringenin seemed to be a new inducer of GRP78 in mammalian cells, and may be a potential therapeutic agent for diseases caused by ER stress such as polyQ diseases.