| 1. |
- Yoshimi, N., et al.
(författare)
-
Cerebrospinal fluid metabolomics identifies a key role of isocitrate dehydrogenase in bipolar disorder: evidence in support of mitochondrial dysfunction hypothesis
- 2016
-
Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:11, s. 1504-1510
-
Tidskriftsartikel (refereegranskat)abstract
- Although evidence for mitochondrial dysfunction in the pathogenesis of bipolar disorder (BD) has been reported, the precise biological basis remains unknown, hampering the search for novel biomarkers. In this study, we performed metabolomics of cerebrospinal fluid (CSF) from male BD patients (n = 54) and age-matched male healthy controls (n = 40). Subsequently, postmortem brain analyses, genetic analyses, metabolomics of CSF samples from rats treated with lithium or valproic acid were also performed. After multivariate logistic regression, isocitric acid (isocitrate) levels were significantly higher in the CSF from BD patients than healthy controls. Furthermore, gene expression of two subtypes (IDH3A and IDH3B) of isocitrate dehydrogenase (IDH) in the dorsolateral prefrontal cortex from BD patients was significantly lower than that of controls, although the expression of other genes including, aconitase (ACO1, ACO2), IDH1, IDH2 and IDH3G, were not altered. Moreover, protein expression of IDH3A in the cerebellum from BD patients was higher than that of controls. Genetic analyses showed that IDH genes (IDH1, IDH2, IDH3A, IDH3B) and ACO genes (ACO1, ACO2) were not associated with BD. Chronic (4 weeks) treatment with lithium or valproic acid in rats did not alter CSF levels of isocitrate, and mRNA levels of Idh3a, Idh3b, Aco1 and Aco2 genes in the rat brain. These findings suggest that abnormality in the metabolism of isocitrate by IDH3A in the mitochondria plays a key role in the pathogenesis of BD, supporting the mitochondrial dysfunction hypothesis of BD. Therefore, IDH3 in the citric acid cycle could potentially be a novel therapeutic target for BD.
|
|
| 2. |
- Ishima, T., et al.
(författare)
-
Abnormal gene expression of BDNF, but not BDNF-AS, in iPSC, neural stem cells and postmortem brain samples from bipolar disorder
- 2021
-
Ingår i: Journal of Affective Disorders. - : Elsevier BV. - 0165-0327. ; 290, s. 61-64
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Brain-derived neurotrophic factor (BDNF) antisense RNA (BDNF-AS) was identified as naturally conserved non-coding antisense RNA that suppresses the transcription of BDNF. Methods: We measured the expression of BDNF mRNA and BDNF-AS mRNA in iPSC and NSC from bipolar disorder (BD) patients and healthy control subjects, and postmortem brain samples such as the corpus callosum, the Brodmann area (BA8), and BA46 from BD patients and age-and sex-matched controls. Results: The expression of BDNF mRNA in iPSC from BD patients (n = 6) was significantly lower than that of control subjects (n = 4) although the expression of BDNF mRNA in NSC from BD patients was significantly higher than that of control subjects. In contrast, there were no changes in the expression of BDNF-AS mRNA in both iPSC and NSC between two groups. The expression of BDNF mRNA in the BA46 from BD patients (n = 35) was significantly lower than that of controls (n = 34) although the expression of BDNF mRNA in the corpus callosum and BA8 was not different between two groups (n = 15). In contrast, there were no changes in expression of BDNF-AS mRNA in the three brain regions between two groups. Interestingly, there were significant positive correlations between BDNF mRNA expression and BDNF-AS mRNA expression in the postmortem brain samples. Limitations: Sample sizes are relatively low. Conclusions: Our data suggest that abnormalities in the expression of BDNF, but not BDNF-AS, play a role in the pathogenesis of BD.
|
|
| 3. |
- Hashimoto, K., et al.
(författare)
-
Increased levels of ascorbic acid in the cerebrospinal fluid of cognitively intact elderly patients with major depression: a preliminary study
- 2017
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Major depressive disorder (MDD) in the elderly is a risk factor for dementia, but the precise biological basis remains unknown, hampering the search for novel biomarkers and treatments. In this study, we performed metabolomics analysis of cerebrospinal fluid (CSF) from cognitively intact elderly patients (N = 28) with MDD and age-and gender-matched healthy controls (N = 18). The CSF levels of 177 substances were measured, while 288 substances were below the detection limit. Only ascorbic acid was significantly different, with higher levels in the MDD group at baseline. There were no correlations between CSF ascorbic acid levels and clinical variables in MDD patients at baseline. At the 3-year follow-up, there was no difference of CSF ascorbic acid levels between the two groups. There was a negative correlation between CSF ascorbic acid and CSF amyloid-beta(42) levels in all subjects. However, there were no correlations between ascorbic acid and other biomarkers (e.g.,amyloid-beta(40), total and phosphorylated tau protein). This preliminary study suggests that abnormalities in the transport and/or release of ascorbic acid might play a role in the pathogenesis of late-life depression.
|
|
