👤 Makoto Usami

We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD. Show less

Alzheimer's disease (AD) is the most common cause of dementia in elderly persons. Since the pathology of AD develops slowly from a preclinical or early phase into a fully expressed clinical syndrome, at the time of diagnosis the disease has been progressing for many years. To facilitate the early diagnosis of AD, we performed protein profiling of blood in patients with mild AD as defined by the Functional Assessment Staging (FAST) scale. Plasma samples from mild AD patients and healthy controls were analyzed using two-dimensional differential gel electrophoresis (2D-DIGE) combined with matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF/MS) followed by peptide mass fingerprinting. Three downregulated proteins were identified: apolipoprotein A-1, alpha-2-HS-glycoprotein, and afamin. Two proteins, including apolipoprotein A-4 and fibrinogen gamma chain, were upregulated in mild AD patients. Our results suggest that altered expression levels of these proteins in plasma may yield candidate biomarkers for the early diagnosis of AD. AD, Alzheimer's disease; FAST, Functional Assessment Staging; 2D-DIGE, two-dimensional differential gel electrophoresis; MALDI-TOF/TOF/MS, matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry; CSF, cerebrospinal fluid; Aβ, amyloid beta; MMSE, Mini Mental State Examination; MRI, magnetic resonance imaging; NINCDS-ADRDA, National Institute for Neurological Diseases and Stroke/Alzheimer's Disease and Related Disorders Association; CHAPS, 3-((3-cholamidopropyl) dimethylammonio)-1-propanesulfonate; DTT, dithiothreitol; SDS-PAGE, SDS-polyacrylamide gel electrophoresis; DIA, differential in-gel analysis; BVA, biological variation analysis; CBB, Coomassie brilliant blue; 2DE, two-dimensional gel electrophoresis; TFA, trifluoroacetic acid; ACTH, adrenocorticotropic hormone; Apo A-1, apolipoprotein A-1; AHSG, alpha-2-HS-glycoprotein; Apo A-4, apolipoprotein A-4; MCI, mild cognitive impairment. Show less

Hyperglycemia induces nonconcordant regulation of renal mitochondrial respiratory complexes, increases oxidative stress, and causes diabetic nephropathy. Hypertension is a complication associated with diabetes and involves glomerular hyperfiltration, the effects of which on mitochondrial respiratory complexes are not well understood. To investigate the effect of glomerular hyperfiltration on renal mitochondrial respiratory complexes, we used the 5/6 nephrectomized BKS. Cg-Dock7 Show less

gp130-dependent signaling is known to play a critical role in the onset of heart failure. In that regard, cardiotrophin-1 (CT-1) activates several signaling pathways via gp130, and induces hypertrophy in neonatal rat cardiomyocytes. Among the mediators activated by CT-1, STAT3 is thought to be important for induction of cell hypertrophy, though its precise function in the CT-1 signaling pathway is not fully understood. In the present study, therefore, to better understand the significance of STAT3 activity in CT-1 signaling, we infected cultured cardiomyocytes with adenoviral vectors harboring a dominant-negative STAT3 mutant or one of two endogenous negative regulators of cytokine signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways [suppressor of cytokine signaling (SOCS) 1 and 3] and then examined their effects on three indexes of CT-1-induced cell hypertrophy: protein synthesis, secretion of brain natriuretic peptide and changes in cell surface area. In control cells, CT-1-induced both STAT3 phosphorylation and cell hypertrophy. Overexpression of dominant-negative STAT3 mutant suppressed CT-1-induced STAT3 phosphorylation, but did not affect cell hypertrophy. On the other hand overexpression of SOCS1 or SOCS3 inhibited both CT-1-induced STAT3 phosphorylation and cell hypertrophy. CT-1 also induced phosphorylations of ERK1/2 and ERK5 in cardiomyocytes, and those, too, were suppressed by overexpression of SOCSs. CT-1-induced cell hypertrophy was suppressed by overexpression of a dominant-negative MEK5 mutant, and not by overexpression of a dominant-negative MEK1 mutant. These findings indicate that the major pathway responsible for the hypertrophic responses to CT-1 is not JAK-STAT3 pathway nor MEK1-ERK1/2 pathway, but MEK5-ERK5 pathway. Show less