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

doi:10.1371/journal.pgen.1005591

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 journal › Article › peer-review

41 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 C_18:1-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 C_18:1-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 language	English (US)
Article number	e1005591
Journal	PLoS genetics
Volume	11
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1005591
State	Published - 2015
Externally published	Yes

ASJC Scopus subject areas

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

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Wang, K., Xu, R., Schrandt, J., Shah, P., Gong, Y. Z., Preston, C., Wang, L., Yi, J. K., Lin, C. L., Sun, W., Spyropoulos, D. D., Rhee, S., Li, M., Zhou, J., Ge, S., Zhang, G., Snider, A. J., Hannun, Y. A., Obeid, L. M., & Mao, C. (2015). Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain. PLoS genetics, 11(10), Article e1005591. https://doi.org/10.1371/journal.pgen.1005591

Wang, K, Xu, R, Schrandt, J, Shah, P, Gong, YZ, Preston, C, Wang, L, Yi, JK, Lin, CL, Sun, W, Spyropoulos, DD, Rhee, S, Li, M, Zhou, J, Ge, S, Zhang, G, Snider, AJ, Hannun, YA, Obeid, LM & Mao, C 2015, 'Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain', PLoS genetics, vol. 11, no. 10, e1005591. https://doi.org/10.1371/journal.pgen.1005591

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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.",

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AU - Schrandt, Jennifer

AU - Shah, Prithvi

AU - Gong, Yong Z.

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AU - Wang, Louis

AU - Yi, Jae Kyo

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AU - Ge, Shaoyu

AU - Zhang, Guofeng

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AU - Hannun, Yusuf A.

AU - Obeid, Lina M.

AU - Mao, Cungui

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AB - 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.

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

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