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

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  1. The paper from Kakiuchi and coworkers is interesting and deserves greater attention. Recent evidence indicates that ER stresses and unfolded protein response (UPR) are associated with genetic or neuronal degenerative diseases such as Alzheimer’s disease and Parkinson's disease. Although it is unclear how the detailed mechanisms of the UPR play roles in the onset of these diseases, this is plausible because misfolded proteins are directly implicated in the pathogenesis of these disorders. In contrast, in bipolar disorder, there has not been any evidence that abnormal proteins are accumulated in patients' brains; therefore, it is important to discover accumulated proteins in the brains to clarify the relationship of the bipolar disorder with the disturbance of the UPR pathway.

    Kakiuchi et al. report that the –116C to G polymorphism of XBP1, a pivotal gene in transcriptional activation of UPR target genes,(1) causes an impairment of its positive feedback system and increases the risk of bipolar disorder. The activation of UPR signaling leads to induction of ER molecular chaperones, including GRP78/BiP. Disturbance of the IRE1-XBP1 pathway never causes the downregulation of BiP mRNA. To my knowledge, the specific XBP1 target, whose induction has been shown to depend completely and solely on the IRE1-XBP1 pathway, is EDEM (ER degradation-enhancing α-mannosidase-like protein).(2) EDEM is known to play pivotal roles in ERAD (ER associated degradation),(3) indicating that impairment of the positive feedback system of XBP1 could affect the degradation of unfolded protein accumulated in the ER. Identification of genes whose expression is downregulated by impaired function of XBP1 will provide novel mechanisms of the bipolar disorder at the molecular level.

    References:

    . A time-dependent phase shift in the mammalian unfolded protein response. Dev Cell. 2003 Feb;4(2):265-71. PubMed.

    . XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001 Dec 28;107(7):881-91. PubMed.

    . EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin. Science. 2003 Feb 28;299(5611):1394-7. PubMed.

  2. ER disturbance may result from protein misfolding or from perturbation in the ER calcium homeostasis. Both events can lead to the activation of one or more of the ER stress sensors, ATF6, PERK and IRE1. This cascade of events activates gadd 153 and eventually leads to impairment of neuronal functions. We have recently shown that lithium, the most prescribed drug for bipolar disorders, targets the ER by preventing Aβ-induced activation of caspase-12 in hippocampus of white New Zealand rabbits (Ghribi et al., 2003. Lithium is also able to prevent the cleavage of caspase-3 that we have demonstrated in the same study to occur in the ER.

    References:

    . Lithium inhibits Abeta-induced stress in endoplasmic reticulum of rabbit hippocampus but does not prevent oxidative damage and tau phosphorylation. J Neurosci Res. 2003 Mar 15;71(6):853-62. PubMed.

  3. The paper from Kakiuchi and coworkers is very interesting for people like us who have been working in the field of ER stress and neurodegenerative diseases. I am amazed that the polymorphism in a UPR (unfolded protein response) molecule may be implicated in the onset of bipolar disorder, and that we could also select a responder for valproate. I believe that this report will bring great benefits to clinical therapy for bipolar patients.

    However, I have a couple of questions on their data. Firstly, I wonder that a discussion about splicing of XBP1 was skipped in this paper. It is reported that XBP1 mRNA is cleaved by IRE1 to remove a 26-nucleotide intron and generate a translational frameshift. The processed mRNA encodes the protein that can act as a transcriptional activator (see Yoshida et al., 2001; Calfon et al., 2002). Many people believe that this splicing process is a critical point for the induction of ER chaperones. Does the increased XBP1 mRNA in the genotype C/C increase the processed mRNA proportionally? I think there are no data about this point.

    Secondly, it is believed that the failure of ER stress response causes apoptotic cell death. Does the genotype G/G increase the likelihood of apoptosis compared to the genotype C/C? However, there has been little reported about morphological changes in bipolar patient brains. Should we suppose that another mechanism is regulated by the ER stress responses?

    In conclusion, this paper opens up new avenues to nonorganic psychiatric disorders in the field of ER stress.

    References:

    . XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001 Dec 28;107(7):881-91. PubMed.

    . IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature. 2002 Jan 3;415(6867):92-6. PubMed.

References

News Citations

  1. Shape-Shifting Prion Protein in Cytosol: Highly Toxic Yet Almost Invisible
  2. New Substrate for Parkin Links Disease to ER Stress

Paper Citations

  1. . The cellular response to protein misfolding in the endoplasmic reticulum. Gene Expr. 1999;7(4-6):293-300. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. . Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat Genet. 2003 Oct;35(2):171-5. PubMed.