ABCA13 dysfunction associated with psychiatric disorders causes impaired cholesterol trafficking

Abstract

ATP-binding cassette subfamily A member 13 (ABCA13) is predicted to be the largest ABC protein, consisting of 5058 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.

Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder

“…The ABC family genes encode transporters that utilize the hydrolysis of ATP as the energy source to transport the substrates across the membrane to maintain the normal physiological functions in various tissues [30]. The ABCA13 encodes a large protein of 5058 amino acids and internalizes cholesterol and gangliosides from the plasma membrane to intracellular vesicles [31]. Knight and colleagues were the first to report the significant association of rare mutations of ABCA13 with SZ, BD, and major depression [32].…”

Identification of loci associated with pathological outcomes in Holstein cattle infected with Mycobacterium avium subsp. paratuberculosis using whole-genome sequence data

“…Using RNA-Seq, we previously observed that the cholesterol route (bta04977) was dysregulated in the ileocecal valve (ICV) of cows with diffuse lesions versus the control group with four upregulated genes matching this route ( APOA1, APOC3, APOA4, APOB ) 34 . In addition, the top upregulated gene in peripheral blood of animals with focal lesions versus control cows was the ATP-Binding Cassette Subfamily A Member 13 ( ABCA13 ), a gene that accelerates cholesterol internalization and accumulation in intracellular vesicles 34 , 44 , 45 . In agreement with our data, recent evidence suggests that MAP-infected macrophages accumulate intracellular cholesterol droplets and depict a foam cell phenotype during infection providing an enriched environment for MAP survival 46 , 47 .…”

Host Genetics Underlying Pathological Outcomes to Mycobacterium Avium Subsp. Paratuberculosis Infection is Governed by Distinct Genetic Variants

“…Using RNA-Seq, we previously detected that the cholesterol route (bta04977) was dysregulated in the ICV of cows with diffuse lesions versus the control group with four upregulated genes matching this route (APOA1, APOC3, APOA4, APOB) [31]. In addition, the top upregulated gene in peripheral blood of animals with focal lesions versus control cows was the cassette subfamily A member 13 (ABCA13), a gene that accelerates cholesterol internalization and accumulation in intracellular vesicles [31][32]41]. In agreement with our data, recent evidence suggests that MAP-infected macrophages accumulate intracellular cholesterol droplets and depict a foam cell phenotype providing an enriched environment for MAP survival [42][43].…”