"Skittish" Abca2 knockout mice display tremor, hyperactivity, and abnormal myelin ultrastructure in the central nervous system.
The ATP-binding cassette transporter 2 (ABCA2) is an endolysosomal protein most highly expressed in the central and peripheral nervous system tissues and macrophages. Previous studies indicated its role in cholesterol/steroid (estramustine, estradiol, and progesterone) trafficking/sequestration, oxidative stress response, and Alzheimer's disease. Developmental studies have shown its expression during macrophage and oligodendrocyte differentiation, processes requiring membrane growth. To determine the in vivo function(s) of this transporter, we generated a knockout mouse from a gene-targeted disruption of the murine ABCA2 gene. Knockout males and females are viable and fertile. However, a non-Mendelian inheritance pattern was shown among male progeny of heterozygous crosses. Compared to wild-type and heterozygous littermates, knockout mice displayed a tremor without ataxia, hyperactivity, and reduced body weight; the latter two phenotypes were more marked in females than in males. This sexual disparity suggests a role for ABCA2 in hormone-dependent neurological and/or developmental pathways. Myelin sheath thickness in the spinal cords of knockout mice was greatly increased compared to that in wild-type mice, while a significant reduction in myelin membrane periodicity (compaction) was observed in both spinal cords and cerebra of knockout mice. Loss of ABCA2 function in vivo resulted in abnormal myelin compaction in spinal cord and cerebrum, an ultrastructural defect that we propose to be the cause of the phenotypic tremor.
Mack
Jody T
JT
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, P.O. Box 250505, Charleston, SC 29425, USA.
Beljanski
Vladimir
V
Soulika
Athena M
AM
Townsend
Danyelle M
DM
Brown
Carol B
CB
Davis
Warren
W
Tew
Kenneth D
KD
D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal; D002490:Central Nervous System / Q000378:metabolism*; D005260:Female; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000737:chemistry / Q000648:ultrastructure*; D019636:Neurodegenerative Diseases / Q000235:genetics; D010641:Phenotype; D011595:Psychomotor Agitation / Q000235:genetics*; D014202:Tremor / Q000235:genetics*
D018528:ATP-Binding Cassette Transporters; C498824:Abca2 protein, mouse