Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions.

Objective: Mutations in nuclear-encoded mitochondrial DNA (mtDNA) polymerase (POLG) are known to cause autosomal dominant chronic progressive external ophthalmoplegia (adCPEO) with accumulation of multiple mtDNA deletions in muscles. However, no animal model with a heterozygous Polg mutation representing mtDNA impairment and symptoms of CPEO has been established. To understand the pathogenic mechanism of CPEO, it is important to determine the age dependency and tissue specificity of mtDNA impairment resulting from a heterozygous mutation in the Polg gene in an animal model.

Attenuated BDNF-induced upregulation of GABAergic markers in neurons lacking Xbp1.

XBP1 is a transcription factor induced by unconventional splicing associated with endoplasmic reticulum stress and plays a role in development. Brain-derived neurotrophic factor (BDNF) causes splicing of Xbp1 mRNA in neurites, and Xbp1 is required for BDNF-induced neurite extension and branching. To search for the molecular mechanisms of how Xbp1 plays a role in neural development, comprehensive gene expression analysis was performed in primary telencephalic neurons obtained from Xbp1 knockout mice at embryonic day 12.

Aberrant endoplasmic reticulum stress response in lymphoblastoid cells from patients with bipolar disorder.

Impaired endoplasmic reticulum (ER) stress response has been suggested as a possible pathophysiological mechanism of bipolar disorder (BD). The expression of ER stress-related genes, spliced form or unspliced form of XBP1, GRP78 (HSPA5), GRP94 (HSP90B1), CHOP (DDIT3), and calreticulin (CALR), were examined in lymphoblastoid cells derived from 59 patients with BD and 59 age- and sex-matched control subjects. Basal mRNA levels and induction by 4 h or 12 h of treatment with two ER stressors, thapsigargin or tunicamycin, were examined using real-time quantitative reverse transcription-polymerase chain reaction.

Quantitative analysis of the 4977-bp common deletion of mitochondrial DNA in postmortem frontal cortex from patients with bipolar disorder and schizophrenia.

Several reports have suggested a role for mitochondrial dysfunction in the pathophysiology of bipolar disorder and schizophrenia. We have focused on the relationship between deleted mitochondrial DNA (mtDNA) and bipolar disorder. To investigate this relationship, we developed a methodology for quantification of the common 4977-bp deletion of mtDNA based on real-time polymerase chain reaction with SYBR Green.

The role of brain-derived neurotrophic factor (BDNF)-induced XBP1 splicing during brain development.

Accumulation of unfolded proteins in the endoplasmic reticulum initiates intracellular signaling termed the unfolded protein response (UPR). Although Xbp1 serves as a pivotal transcription factor for the UPR, the physiological role of UPR signaling and Xbp1 in the central nervous system remains to be elucidated. Here, we show that Xbp1 mRNA was highly expressed during neurodevelopment and activated Xbp1 protein was distributed throughout developing neurons, including neurites.

Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with schizophrenia in the Japanese population.

Schizophrenia and bipolar disorder share common genetic background. Several loci such as 18p11, 13q32, and 22q11-13 were commonly linked with these diseases. Since mitochondrial dysfunction has been suggested in both of these disorders, NDUFV2 at 18p11, encoding a subunit of the complex I, NADH ubiquinone oxidoreductase, is a candidate gene for these diseases.

Quantitative analysis of mitochondrial DNA deletions in the brains of patients with bipolar disorder and schizophrenia.

Several clinical, genetic and neuroimaging studies implicate mitochondrial dysfunction in the pathophysiology of bipolar disorder and schizophrenia. It has been reported that a mitochondrial DNA (mtDNA) deletion of 4,977 bp, known as the 'common deletion', is associated with both mental illnesses. A lack of normal age-related accumulation of this deletion in schizophrenia and increased occurrence of the common deletion in bipolar disorder have been reported.

Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with bipolar disorder in Japanese and the National Institute of Mental Health pedigrees.

Background: Linkage with 18p11 is one of the replicated findings in molecular genetics of bipolar disorder. Because mitochondrial dysfunction has been suggested in bipolar disorder, NDUFV2 at 18p11, encoding a subunit of the complex I, reduced nicotinamide adenine dinucleotide (NADH)ubiquinone oxidoreductase, is a candidate gene for this disorder. We previously reported that a polymorphism in the upstream region of NDUFV2, -602G> A, was associated with bipolar disorder in Japanese subjects; however, functional significance of -602G> A was not known.