ABCA13 dysfunction associated with psychiatric disorders causes impaired cholesterol trafficking

Large transporter protein linked to schizophrenia. 京都大学プレスリリース. 2021-01-07.ABCA13の異常によるコレステロール輸送障害が統合失調症を引き起こすことを解明. 京都大学プレスリリース. 2021-01-08.ATP-binding cassette subfamily A member 13 (ABCA13) is predicted to be the largest ABC protein, consisting of 5, 058 amino acids and a long N-terminal region. Mutations in the ABCA13 gene were reported to increase the susceptibility to schizophrenia, bipolar disorder and major depression. However, little is known about the molecular functions of ABCA13 or how they associate with psychiatric disorders. Here, we examined the biochemical activity of ABCA13 using HEK293 cells transfected with mouse ABCA13. The expression of ABCA13 induced the internalization of cholesterol and gangliosides from the plasma membrane to intracellular vesicles. Cholesterol internalization by ABCA13 required the long N-terminal region and ATP hydrolysis. To examine the physiological roles of ABCA13, we generated Abca13 KO mice using CRISPR/Cas and found that these mice exhibited deficits of prepulse inhibition. Vesicular cholesterol accumulation and synaptic vesicle endocytosis were impaired in primary cultures of Abca13 KO cortical neurons. Furthermore, mutations in ABCA13 gene associated with psychiatric disorders disrupted the protein’s subcellular localization and impaired cholesterol trafficking. These findings suggest that ABCA13 accelerates cholesterol internalization by endocytic retrograde transport in neurons and that loss-of-this function is associated with the pathophysiology of psychiatric disorders

Adiponectin Protein Exists in Aortic Endothelial Cells

<div><p>Aims</p><p>Inflammation is closely associated with the development of atherosclerosis and metabolic syndrome. Adiponectin, an adipose-derived secretory protein, possesses an anti-atherosclerotic property. The present study was undertaken to elucidate the presence and significance of adiponectin in vasculature.</p><p>Methods and Results</p><p>Immunofluorescence staining was performed in aorta of wild-type (WT) mice and demonstrated that adiponectin was co-stained with CD31. Thoracic aorta was cut through and then aortic intima was carefully shaved from aorta. Western blotting showed the existence of adiponectin protein in aortic intima, while there was no adiponectin mRNA expression. Adiponectin knockout (Adipo-KO) and WT mice were administered with a low-dose and short-term lipopolysaccharide (LPS) (1 mg/kg of LPS for 4 hours). The endothelium vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were highly increased in Adipo-KO mice compared to WT mice after LPS administration.</p><p>Conclusions</p><p>Adiponectin protein exists in aortic endothelium under steady state and may protect vasculature from the initiation of atherosclerosis.</p></div

Effect of LPS on endothelial adhesion molecules in aortic intima.

<p>Aortic intima of wild-type (WT) or adiponectin knockout (Adipo-KO) mice were removed at 4 hours after LPS administration and were subjected to RT-PCR (A) and western blotting (B). Values are mean ± SEM; n = 6 for each group. * <i>P</i><0.05, compared with the values of WT mice with saline treatment; ‡ <i>P</i><0.05, compared with the values of WT mice with LPS administration group.</p

Localization of adiponectin in aorta.

<p>A, Dual-immunofluorescence was performed in wild-type (WT) and adiponectin knockout (Adipo-KO) mice as described in Materials and Methods. B, High magnification images of aortic intima using confocal laser microscope were obtained from WT mice. Green, adiponectin; blue, DAPI; red, CD31.</p