The risk of developing bipolar disorder appears to increase in people who carry a particular polymorphism of a transcription factor that aids in the clearance of "junk" protein from the endoplasmic reticulum. In the online edition of Nature Genetics, a research team from several institutions in Japan reports that the variation of the protein XBP1 appears to interfere with a feedback mechanism wherein XBP1 and other proteins upregulate the expulsion of unfolded proteins from the ER. (For review, see Welihinda et al., 1999.)
The "unfolded protein response" (or ER stress response) has piqued the interest of neurodegeneration researchers who suspect that a buildup of misfolded protein inside the cell can be toxic (see, for example, ARF related news story or ARF news story). The ER stress response is mediated by chaperone proteins, most notably HSPA5 (also known as GRP78 or BiP). Normally, XBP1 helps upregulate HSPA5 levels in response to stress. The Japanese researchers discovered the role of XBP1 when they examined gene activity in pairs of twins discordant for bipolar disorder. DNA microarrays revealed that genes related to the ER stress response were downregulated in the affected twins. When they examined a larger group of subjects in a case control study (n = 648), they found that a single nucleotide polymorphism (116 C > G) in the XBP1 gene was significantly associated with bipolar disorder (OR 4.6; 95 percent CI 2.1 - 10.2). The polymorphism is in the promoter region and affects the putative binding site of XBP1.
In subsequent experiments with cells in culture, the researchers found that, relative to the C allele, possession of the G allele reduced XBP1-dependent transcription activity, and reduced the capacity of the XBP1 gene to be upregulated in the face of experimentally induced ER stress. Of three bipolar disorder drugs tested, only valproate was able to overcome the handicap presented by the G allele in ER stress situations.
"Our results strongly suggest a pathophysiological role for the XBP1 loop in the ER stress response pathway in bipolar disorder," write the authors, citing the need for more research on the function of XBP1 and ER stress response in the nervous system.—Hakon Heimer