title: Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain.
abstract: Dyshomeostasis of both ceramides and sphingosine-1-phosphate (S1P) in the brain has been implicated in aging-associated neurodegenerative disorders in humans. However, mechanisms that maintain the homeostasis of these bioactive sphingolipids in the brain remain unclear. Mouse alkaline ceramidase 3 (Acer3), which preferentially catalyzes the hydrolysis of C18:1-ceramide, a major unsaturated long-chain ceramide species in the brain, is upregulated with age in the mouse brain. Acer3 knockout causes an age-dependent accumulation of various ceramides and C18:1-monohexosylceramide and abolishes the age-related increase in the levels of sphingosine and S1P in the brain; thereby resulting in Purkinje cell degeneration in the cerebellum and deficits in motor coordination and balance. Our results indicate that Acer3 plays critically protective roles in controlling the homeostasis of various sphingolipids, including ceramides, sphingosine, S1P, and certain complex sphingolipids in the brain and protects Purkinje cells from premature degeneration.
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America; Stony Brook Cancer Center, Stony Brook, New York, United States of America; Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America; Stony Brook Cancer Center, Stony Brook, New York, United States of America.
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America; Stony Brook Cancer Center, Stony Brook, New York, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schrandt
authors.affiliation: Division of Rehabilitation Sciences, Department of Physical Therapy, School of Health Technology and Management, Stony Brook University, Stony Brook, New York, United States of America; Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Prithvi
authors.initials: P
authors.lastname: Shah
authors.affiliation: Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Yong Z
authors.initials: YZ
authors.lastname: Gong
authors.affiliation: Division of Rehabilitation Sciences, Department of Physical Therapy, School of Health Technology and Management, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Chet
authors.initials: C
authors.lastname: Preston
authors.affiliation: Division of Rehabilitation Sciences, Department of Physical Therapy, School of Health Technology and Management, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Louis
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America; Stony Brook Cancer Center, Stony Brook, New York, United States of America.
authors.forename: Jae Kyo
authors.initials: JK
authors.lastname: Yi
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America; Stony Brook Cancer Center, Stony Brook, New York, United States of America.
authors.forename: Chih-Li
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Demetri D
authors.initials: DD
authors.lastname: Spyropoulos
authors.affiliation: Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Rhee
authors.affiliation: Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Mingsong
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Shaoyu
authors.initials: S
authors.lastname: Ge
authors.affiliation: Biomedical Engineering and Physical Science Shared Resource, National Institute of Biomedical Imaging and Bioengineering, National Institute of Health, Bethesda, Maryland, United States of America.
authors.forename: Guofeng
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America; Stony Brook Cancer Center, Stony Brook, New York, United States of America; Northport Veterans Affairs Medical Center, Northport, New York, United States of America.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Snider
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America; Stony Brook Cancer Center, Stony Brook, New York, United States of America.
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America; Stony Brook Cancer Center, Stony Brook, New York, United States of America; Northport Veterans Affairs Medical Center, Northport, New York, United States of America.
authors.forename: Lina M
authors.initials: LM
authors.lastname: Obeid
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America; Stony Brook Cancer Center, Stony Brook, New York, United States of America.
authors.forename: Cungui
authors.initials: C
authors.lastname: Mao
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055574:Alkaline Ceramidase / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002518:Ceramides / Q000235:genetics / Q000378:metabolism; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D013107:Sphingolipids / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism
chemical_list: D002518:Ceramides; D008246:Lysophospholipids; D013107:Sphingolipids; C060506:sphingosine 1-phosphate; D055574:Alkaline Ceramidase; D013110:Sphingosine