Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain

Kai Wang, Ruijuan Xu, Jennifer Schrandt, Prithvi Shah, Yong Z. Gong, Chet Preston, Louis Wang, Jae Kyo Yi, Chih Li Lin, Wei Sun, Demetri D. Spyropoulos, Soyoung Rhee, Mingsong Li, Jie Zhou, Shaoyu Ge, Guofeng Zhang, Ashley J. Snider, Yusuf A. Hannun, Lina M. Obeid, Cungui Mao

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish (US)
Article numbere1005591
JournalPLoS genetics
Volume11
Issue number10
DOIs
StatePublished - 2015
Externally publishedYes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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