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. 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. ATP-binding cassette (ABC) proteins constitute a transporter superfamily that plays important physiological roles in all living organisms (1Ueda K. ABC proteins protect the human body and maintain optimal health.Biosci. Biotechnol. Biochem. 2011; 75: 401-409Crossref PubMed Scopus (62) Google Scholar, 2Schneider E. Hunke S. ATP-binding-cassette (ABC) transport systems: functional and structural aspects of the ATP-hydrolyzing subunits/domains.FEMS Microbiol. Rev. 1998; 22: 1-20Crossref PubMed Google Scholar). ABC proteins couple the energy of ATP binding and hydrolysis to many biological processes such as the translocation of various substrates including lipids, ions, peptides, and xenobiotics (3Davidson A.L. Dassa E. Orelle C. Chen J. Structure, function, and evolution of bacterial ATP-binding cassette systems.Microbiol. Mol. Biol. Rev. 2008; 72: 317-364Crossref PubMed Scopus (959) Google Scholar). Defects in the function and expression of ABC proteins are related to various diseases (1Ueda K. ABC proteins protect the human body and maintain optimal health.Biosci. Biotechnol. Biochem. 2011; 75: 401-409Crossref PubMed Scopus (62) Google Scholar). ATP-binding cassette subfamily A member 13 (ABCA13) is a transmembrane protein with the typical structure of ABC proteins: two transmembrane domains (TMDs) and two nucleotide-binding domains (NBDs) characterized by Walker A, Walker B, and ABC signature motifs (4Prades C. Arnould I. Annilo T. Shulenin S. Chen Z.Q. Orosco L. Triunfol M. Devaud C. Maintoux-Larois C. Lafargue C. Lemoine C. Denèfle P. Rosier M. Dean M. The human ATP binding cassette gene ABCA13, located on chromosome 7p12.3, encodes a 5058 amino acid protein with an extracellular domain encoded in part by a 4.8-kb conserved exon.Cytogenet. Genome Res. 2002; 98: 160-168Crossref PubMed Scopus (29) Google Scholar). ABCA13 is predicted to be the largest member of the ABC protein family, and the human form includes 5058 amino acid residues and a long N-terminal region. In addition, alternative ABCA13 transcripts and protein lacking the N-terminal region were also reported (5Maeß M.B. Stolle K. Cullen P. Lorkowski S. Evidence for an alternative genomic structure, mRNA and protein sequence of human ABCA13.Gene. 2013; 515: 298-307Crossref PubMed Scopus (6) Google Scholar, 6Barros S.A. Tennant R.W. Cannon R.E. Molecular structure and characterization of a novel murine ABC transporter, Abca13.Gene. 2003; 307: 191-200Crossref PubMed Scopus (20) Google Scholar). The calculated molecular masses of full-size and shorter human ABCA13 are about 570 kDa and 260 kDa, respectively. ABCA13 is expressed in the human trachea, testis, bone marrow, brain, and other tissues (4Prades C. Arnould I. Annilo T. Shulenin S. Chen Z.Q. Orosco L. Triunfol M. Devaud C. Maintoux-Larois C. Lafargue C. Lemoine C. Denèfle P. Rosier M. Dean M. The human ATP binding cassette gene ABCA13, located on chromosome 7p12.3, encodes a 5058 amino acid protein with an extracellular domain encoded in part by a 4.8-kb conserved exon.Cytogenet. Genome Res. 2002; 98: 160-168Crossref PubMed Scopus (29) Google Scholar, 5Maeß M.B. Stolle K. Cullen P. Lorkowski S. Evidence for an alternative genomic structure, mRNA and protein sequence of human ABCA13.Gene. 2013; 515: 298-307Crossref PubMed Scopus (6) Google Scholar, 7Knight H.M. Pickard B.S. Maclean A. Malloy M.P. Soares D.C. McRae A.F. Condie A. White A. Hawkins W. McGhee K. van Beck M. MacIntyre D.J. Starr J.M. Deary I.J. Visscher P.M. et al.A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression.Am. J. Hum. Genet. 2009; 85: 833-846Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). ABCA13 belongs to the subfamily C. E. The and protein functions and associated PubMed Scopus Google Scholar). proteins in this subfamily are reported to transport M. ATP-binding cassette proteins in and PubMed Scopus Google including cholesterol and by S. T. K. M. T. M. S. K. of mutations of in the extracellular domain on subcellular and ATP Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, P. binding of cholesterol and plasma membrane in cells Biol. Full Text Full Text PDF PubMed Scopus Google by M. as a transporter in Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. K. and in ATP binding cassette associated with Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, E. A. M. A. A. S. M. mutations and of Res. 2011; PubMed Scopus Google Scholar, T. J. S. is a body membrane protein in human PubMed Scopus Google by S. M. is the for the ABC transporter Biol. Full Text Full Text PDF PubMed Scopus Google and by M. M. K. by human Mol. Biol. PubMed Scopus Google Scholar, M. P. Chen W. ATP-binding cassette transporter and cholesterol Biol. 2003; Full Text Full Text PDF PubMed Scopus Google and by M. K. M. K. K. Mutations in transporter in and functional by gene PubMed Scopus Google Scholar). These findings suggest that ABCA13 However, the function of ABCA13 is rare variants of human ABCA13 are related to susceptibility for schizophrenia, bipolar disorder, and major H.M. Pickard B.S. Maclean A. Malloy M.P. Soares D.C. McRae A.F. Condie A. White A. Hawkins W. McGhee K. van Beck M. MacIntyre D.J. Starr J.M. Deary I.J. Visscher P.M. et al.A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression.Am. J. Hum. Genet. 2009; 85: 833-846Abstract Full Text Full Text PDF PubMed Scopus (93) Google on of these rare variants to this in an S. I. L. J. of rare variants ABCA13 in and bipolar 2011; PubMed Scopus Google Scholar). A the ABCA13 impaired and and that are associated with S. C. M. A. M. The of the in a of with ABCA13 J. PubMed Scopus Google Scholar, K. I. A. A. A. M. and of in PubMed Scopus Google Scholar). However, the a in associated with disorders including disorder, the ABCA13 the in a of is to human ABCA13, induced and I. A. M. T. M. M. for psychiatric disorders including by of ATP-binding cassette protein PubMed Scopus Google Scholar). However, in the amino acid sequence and protein of are to that of ABCA13. In this to the molecular functions of ABCA13, we examined the subcellular localization and function of ABCA13 in HEK293 cells transfected with mouse ABCA13. To the physiological roles of ABCA13, we generated Abca13 KO mice using the proteins and the of ABCA13 on In addition, we examined the intracellular cholesterol and synaptic vesicle endocytosis in Abca13 KO cortical ABCA13 to the of mutations associated with psychiatric disorders on ABCA13 function, that with in the subcellular localization of and cholesterol by ABCA13. To the of ABCA13 expressed in using mouse Abca13 is A major kDa, is with the predicted molecular of full-size ABCA13 that ABCA13 is expressed as a protein the long N-terminal region in To the biochemical activity of full-size ABCA13, we examined the protein's subcellular HEK293 cells were transfected with a mouse ABCA13 amino a of to ABCA13 expressed in that ABCA13 in intracellular in HEK293 cells of the subfamily important roles in transport processes C. E. The and protein functions and associated PubMed Scopus Google Scholar, S. T. K. M. T. M. S. K. of mutations of in the extracellular domain on subcellular and ATP Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, P. binding of cholesterol and plasma membrane in cells Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, M. as a transporter in Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. K. and in ATP binding cassette associated with Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, E. A. M. A. A. S. M. mutations and of Res. 2011; PubMed Scopus Google Scholar, T. J. S. is a body membrane protein in human PubMed Scopus Google Scholar, S. M. is the for the ABC transporter Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. K. by human Mol. Biol. PubMed Scopus Google Scholar, M. P. Chen W. ATP-binding cassette transporter and cholesterol Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. M. K. K. Mutations in transporter in and functional by gene PubMed Scopus Google Scholar). To ABCA13 is in we the intracellular cholesterol in and HEK293 cells using the were with the in the other the of in were in The reported to membrane domains L. E. S. K. K. I. W. identify of plasma membrane Biol. PubMed Scopus Google Scholar, T. T. for cholesterol and Res. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). the ABCA13 were also with in that in cells with cells These suggest that expressed ABCA13 cholesterol accumulation in vesicles. To examine human ABCA13 is in intracellular and intracellular cholesterol we a human that ABCA13 with HEK293 in intracellular ABCA13 were with These that expressed human ABCA13 cholesterol accumulation in intracellular mouse ABCA13. are the plasma membrane and subcellular E. cholesterol and Rev. Mol. Biol. 2008; PubMed Scopus Google Scholar, L. J.M. and an part of Full Text Full Text PDF PubMed Scopus Google Scholar). the plasma membrane of cholesterol and plasma membrane in cholesterol transport and PubMed Google we that the cholesterol in by ABCA13 from the plasma To this we to cholesterol in living to cholesterol of the of the plasma in living cells M. that is required for the of PubMed Scopus Google Scholar). we found and in in HEK293 cells in transfected cells the with cholesterol from the plasma membrane I. of to plasma membrane cholesterol and PubMed Scopus Google in binding of to the were These suggest that ABCA13 accelerates the internalization of cholesterol from the plasma gangliosides are known to form cholesterol the plasma membrane K. and Rev. Mol. Biol. PubMed Scopus Google Scholar, A. J. M. K. S. T. and in the living membrane form to cholesterol and Biol. PubMed Scopus Google Scholar, M. M. A. W. K. A. et of gangliosides with a Biol. PubMed Scopus Google we examined gangliosides such as and were also HEK293 cells transfected with to ABCA13 or were with or M. M. A. W. K. A. et of gangliosides with a Biol. PubMed Scopus Google and were in ABCA13 internalization in to to gangliosides D.J. E. on the and of bacterial Microbiol. PubMed Scopus Google also to ABCA13 These suggest ABCA13 also the intracellular of cells were with a that is as a for endocytic and J. T. M. and of endocytosis in PubMed Scopus Google Scholar, W. S. Chen plasma membrane and Mol. Biol. PubMed Scopus Google we found in ABCA13 The of cholesterol to in HEK293 cells by ABCA13 expression that ABCA13 cholesterol These suggest that ABCA13 accelerates the internalization of by endocytic retrograde reported that ABCA13 is also expressed as a lacking the long N-terminal from (5Maeß M.B. Stolle K. Cullen P. Lorkowski S. Evidence for an alternative genomic structure, mRNA and protein sequence of human ABCA13.Gene. 2013; 515: 298-307Crossref PubMed Scopus (6) Google Scholar, 6Barros S.A. Tennant R.W. Cannon R.E. Molecular structure and characterization of a novel murine ABC transporter, Abca13.Gene. 2003; 307: 191-200Crossref PubMed Scopus (20) Google Scholar). we the long N-terminal region is required for ABCA13 ABCA13 the N-terminal region generated and transfected HEK293 that ABCA13 expressed as a kDa protein and that localization that the N-terminal region is required for the localization of ABCA13 to intracellular vesicles. ABC proteins couple the energy of ATP binding and hydrolysis to a of biological functions (3Davidson A.L. Dassa E. Orelle C. Chen J. Structure, function, and evolution of bacterial ATP-binding cassette systems.Microbiol. Mol. Biol. Rev. 2008; 72: 317-364Crossref PubMed Scopus (959) Google Scholar). examined cholesterol internalization on ATP hydrolysis by ABCA13. a in in and mutations in in conserved residues in the Walker A for ATP binding and hydrolysis were by K. M. K. and activity of human Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, T. A. K. a of ATP in human Biol. Full Text Full Text PDF PubMed Scopus Google These proteins were expressed and to the intracellular ABCA13 However, with the ATP These suggest that cholesterol internalization is on ATP hydrolysis by ABCA13. To the physiological of ABCA13, we examined the of ABCA13 on by Abca13 KO mice using the CRISPR/Cas on the of A. M. of mice by of and 2013; PubMed Scopus Google Scholar, S.A. M. K. M. T. M. for a mouse by CRISPR/Cas PubMed Scopus Google Scholar). To full-size amino and amino mouse to of the Abca13 gene to mutations the and Abca13 were of and Abca13 gene mutations were by a an in to a in The were in for and for KO using the brain, and bone to the of ABCA13 protein A major of ABCA13 kDa in mice in KO The kDa in and Abca13 KO mice were to be the the of ABCA13 and the predicted molecular of mouse ABCA13 is These that the induced by the CRISPR/Cas in the of ABCA13 Abca13 KO mice were and to and that variants of human ABCA13 are related to psychiatric disorders H.M. Pickard B.S. Maclean A. Malloy M.P. Soares D.C. McRae A.F. Condie A. White A. Hawkins W. McGhee K. van Beck M. MacIntyre D.J. Starr J.M. Deary I.J. Visscher P.M. et al.A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression.Am. J. Hum. Genet. 2009; 85: 833-846Abstract Full Text Full Text PDF PubMed Scopus (93) Google we examined Abca13 KO mice using a of including body and and found in for the the of the by a prepulse the is a of including human and S. K. J. J. in psychiatric from Res. 2013; PubMed Scopus Google Scholar). The of prepulse in with psychiatric disorders such as and bipolar and in of S. K. J. J. in psychiatric from Res. 2013; PubMed Scopus Google Scholar, W. A. deficits in bipolar with Full Text Full Text PDF PubMed Scopus Google Scholar, and mouse of Res. 2009; PubMed Scopus Google Scholar). In the and Abca13 KO mice were in the Abca13 KO mice of prepulse These that Abca13 KO mice To examine the of ABCA13 on intracellular cholesterol in primary mouse cortical neurons in were with and with in Abca13 KO neurons were with neurons. of that the of in Abca13 KO neurons These that ABCA13 to accumulation of cholesterol in cortical neurons. the of a for synaptic vesicle endocytosis L. M.P. Vesicular are for synaptic vesicle PubMed Scopus Google Scholar). we ABCA13 the endocytosis of synaptic using cortical neurons in were with in to the synaptic with S. of synaptic vesicle using and synaptic Scholar). in neurons synaptic vesicle and in Abca13 KO neurons were with neurons that of in Abca13 KO neurons These suggest that ABCA13 synaptic vesicle endocytosis in cortical neurons. variants of human ABCA13 were reported to increase the susceptibility to schizophrenia, bipolar disorder, and major H.M. Pickard B.S. Maclean A. Malloy M.P. Soares D.C. McRae A.F. Condie A. White A. Hawkins W. McGhee K. van Beck M. MacIntyre D.J. Starr J.M. Deary I.J. Visscher P.M. et al.A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression.Am. J. Hum. Genet. 2009; 85: 833-846Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). mutations and are in bipolar and is in To examine the of mutations associated with psychiatric disorders on the function of ABCA13, and were the amino acid residues of mouse ABCA13 and in human ABCA13 is conserved in mouse ABCA13, examined in this and proteins were expressed in HEK293 cells to intracellular and localization In the of and intracellular cholesterol accumulation in the with localization of that cholesterol accumulation in cells with ABCA13 A of the of ABCA13 and of in cells the of the ABCA13 on the However, the ABCA13 These suggest that mutations associated with psychiatric disorders the subcellular localization or function of ABCA13. that rare coding variants of human ABCA13 to the of schizophrenia, bipolar disorder, and major H.M. Pickard B.S. Maclean A. Malloy M.P. Soares D.C. McRae A.F. Condie A. White A. Hawkins W. McGhee K. van Beck M. MacIntyre D.J. Starr J.M. Deary I.J. Visscher P.M. et al.A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression.Am. J. Hum. Genet. 2009; 85: 833-846Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). However, little is known about the molecular functions of ABCA13 or with psychiatric disorders. In this we found that ABCA13 the internalization of cholesterol and gangliosides by endocytic retrograde In addition, we found that Abca13 KO mice exhibited deficits of prepulse and that ABCA13 impaired synaptic vesicle mutations of ABCA13 associated with psychiatric disorders impaired the protein's subcellular localization and are in many important physiological processes including and and the intracellular of is to and functions E. cholesterol and Rev. Mol. Biol. 2008; PubMed Scopus Google Scholar, and intracellular of 2011; PubMed Scopus Google Scholar, S. K. is by Biotechnol. Biochem. PubMed Scopus Google Scholar, M. T. S. C. L. L. of to PubMed Scopus Google Scholar). reported that intracellular cholesterol to the the cholesterol by retrograde cholesterol transport from the plasma membrane to the S. T. M. T. T. K. K. S. in the retrograde and the Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). In this we found that ABCA13 accelerates the internalization of cholesterol and gangliosides from the plasma membrane to intracellular vesicles. These suggest that ABCA13 plays an important for by endocytic retrograde However, the for retrograde transport to be that the plasma membrane and intracellular endocytic is in the plasma membrane S. and intracellular of the Res. Full Text Full Text PDF PubMed Google Scholar, M. K. K. of to 2009; PubMed Scopus Google Scholar). endocytic to the intracellular of these is a that ABCA13 the plasma membrane endocytic of cholesterol and gangliosides to trafficking. The of human ABCA13 gene is the gene and encodes an ABC protein of 5058 amino acids (4Prades C. Arnould I. Annilo T. Shulenin S. Chen Z.Q. Orosco L. Triunfol M. Devaud C. Maintoux-Larois C. Lafargue C. Lemoine C. Denèfle P. Rosier M. Dean M. The human ATP binding cassette gene ABCA13, located on chromosome 7p12.3, encodes a 5058 amino acid protein with an extracellular domain encoded in part by a 4.8-kb conserved exon.Cytogenet. Genome Res. 2002; 98: 160-168Crossref PubMed Scopus (29) Google Scholar). that the gene about of genomic and for a protein of amino acids (5Maeß M.B. Stolle K. Cullen P. Lorkowski S. Evidence for an alternative genomic structure, mRNA and protein sequence of human ABCA13.Gene. 2013; 515: 298-307Crossref PubMed Scopus (6) Google Scholar). findings that ABCA13 with the long N-terminal region is expressed in mice and internalization to intracellular vesicles. the of shorter ABCA13, they for the physiological of ABCA13. The N-terminal region to known human proteins or that ABCA13 with other proteins for the localization and cholesterol in prepulse are in and of various psychiatric disorders including and as a for C. T. S. A. M. T. of the of protein in using Res. PubMed Scopus Google Scholar). The impaired prepulse in Abca13 KO mice we that the of ABCA13 is related to the pathophysiology of psychiatric disorders. Abca13 KO mice exhibited a and such as loss to to the of prepulse inhibition. Furthermore, we found that the body and for the prepulse of Abca13 KO mice were that the of prepulse to in body function, or These findings suggest that ABCA13 the function in that ABCA13 cholesterol accumulation in intracellular and accelerates the endocytosis of synaptic vesicle in cortical neurons. Cholesterol is in the membrane of synaptic S. M. K. M. S. P. S.A. et of a Full Text Full Text PDF PubMed Scopus Google and the of cholesterol in synaptic a on synaptic functions including and of synaptic P. A. Cholesterol and synaptic vesicle Biol. PubMed Google Scholar). are with the that is required for synaptic vesicle L. M.P. Vesicular are for synaptic vesicle PubMed Scopus Google Scholar). Mutations in synaptic vesicle are to psychiatric disorders including and bipolar of synaptic vesicle in PubMed Scopus Google Scholar, as Rev. PubMed Scopus Google Scholar). these of synaptic vesicle by ABCA13 to the pathophysiology of psychiatric disorders. be to examine activity and in Abca13 KO mice in to the localization of ABCA13 in mouse to impaired synaptic vesicle endocytosis to psychiatric disorders. the of cholesterol to in HEK293 cells by ABCA13 expression we the that ABCA13 cholesterol or in neurons. to examine this in the the mouse ABCA13 is The mutations in ABCA13 we and were they increase the susceptibility to and bipolar H.M. Pickard B.S. Maclean A. Malloy M.P. Soares D.C. McRae A.F. Condie A. White A. Hawkins W. McGhee K. van Beck M. MacIntyre D.J. Starr J.M. Deary I.J. Visscher P.M. et al.A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression.Am. J. Hum. Genet. 2009; 85: 833-846Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). found that these mutations impaired the subcellular localization or function of ABCA13. is predicted to be located the (4Prades C. Arnould I. Annilo T. Shulenin S. Chen Z.Q. Orosco L. Triunfol M. Devaud C. Maintoux-Larois C. Lafargue C. Lemoine C. Denèfle P. Rosier M. Dean M. The human ATP binding cassette gene ABCA13, located on chromosome 7p12.3, encodes a 5058 amino acid protein with an extracellular domain encoded in part by a 4.8-kb conserved exon.Cytogenet. Genome Res. 2002; 98: 160-168Crossref PubMed Scopus (29) Google the structure of the transmembrane to ABCA13 the other and are located in the are for ATP binding and hydrolysis. is located of the Walker of and conserved in the subfamily M. J. M. K. The of of ABCA13 on the function of the ABC Biotechnol. Biochem. PubMed Scopus Google Scholar). The of the amino acid in the protein's subcellular localization and function M. J. M. K. The of of ABCA13 on the function of the ABC Biotechnol. Biochem. PubMed Scopus Google Scholar). with that that in ABCA13 the subcellular localization and cholesterol accumulation in that this amino acid is for protein of the Walker A and motifs of in ABCA13 subcellular localization impaired cholesterol trafficking. of the amino acid in on that protein's function M. J. M. K. The of of ABCA13 on the function of the ABC Biotechnol. Biochem. PubMed Scopus Google that this to ABCA13. To we found that full-size ABCA13 is expressed in and accelerates the internalization of cholesterol and gangliosides from the plasma membrane to intracellular vesicles. ABCA13 gene mutations associated with psychiatric disorders impaired the subcellular localization and function of ABCA13. these findings the biological function of ABCA13. In addition, Abca13 KO mice exhibited deficits in prepulse and ABCA13 impaired synaptic vesicle that a loss of function of ABCA13 is associated with the pathophysiology of psychiatric disorders and that the Abca13 KO mice a of psychiatric disorders. on the function of ABCA13 to the of novel for psychiatric disorders. To mouse ABCA13, generated the of mouse ABCA13 M. J. M. K. The of of ABCA13 on the function of the ABC Biotechnol. Biochem. PubMed Scopus Google Scholar). To human ABCA13, from from from and were from from from to and were from and were as reported M. M. A. W. K. A. et of gangliosides with a Biol. PubMed Scopus Google Scholar). The the of mouse Abca13 gene by using mouse as a The the of The of in residues were from the generated by and other Abca13 were generated by using the The expression for domain T. T. for cholesterol and Res. 2011; Full Text Full Text PDF PubMed Scopus Google a from The and Abca13 were by the of as A. M. of mice by of and 2013; PubMed Scopus Google Scholar). 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M. of mice by of and 2013; PubMed Scopus Google Scholar). mouse Abca13 using K. K. for CRISPR/Cas with PubMed Scopus Google Scholar). and were the of Mutations on Abca13 were by KO mice were from a and for the in with and as a mice were and to were of and were in with from the of for and the of The were by using genomic and and as and of and were and the brain, and bone cells were and with were protein A to the and prepulse inhibition. were in a for The to a for with the of the prepulse The the as the The in The of the The prepulse the and or of prepulse and were and in The were by an of of the and cholesterol using or by were by or are the The that they of with the of this of for of the of for with the for M. and K. the M. the M. and J. K. in biological and mouse K. and A. in M. M. and K. M. and K. the the by and

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