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

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 - PLoS Genet. (2015)

Bottom Line: However, mechanisms that maintain the homeostasis of these bioactive sphingolipids in the brain remain unclear.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Acer3 is upregulated with age in the mouse brain.A. mRNA levels of the alkaline ceramidases Acer1, Acer2, and Acer3 in the cerebra and cerebella of young [6 weeks (6W) of age] versus middle-aged mice [8 months (8M) of age] Note that the mRNA levels of Acer3 but not Acer1 or Acer2 were increased in mice at 8M of age compared to at 6W. B. Acer3 mRNA levels in the cerebellum versus the cerebrum of 6W or 8M-old mice. Note that Acer3 mRNA levels were higher in the cerebellum than in the cerebrum in the same mouse at either 6W or 8M of age. C. Alkaline ceramidase activity on NBD-C12-PHC in the brains of young (6W) versus middle-aged mice (8M). Note that the alkaline ceramidase activity was higher in both cerebrum and cerebellum in 8M-old-mice compared to 6W-old mice and that the alkaline ceramidase activity was higher in the cerebellum than in the cerebrum in mice at either age. Data in A, B, and C represent mean values ± SD, n = 3.
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pgen.1005591.g001: Acer3 is upregulated with age in the mouse brain.A. mRNA levels of the alkaline ceramidases Acer1, Acer2, and Acer3 in the cerebra and cerebella of young [6 weeks (6W) of age] versus middle-aged mice [8 months (8M) of age] Note that the mRNA levels of Acer3 but not Acer1 or Acer2 were increased in mice at 8M of age compared to at 6W. B. Acer3 mRNA levels in the cerebellum versus the cerebrum of 6W or 8M-old mice. Note that Acer3 mRNA levels were higher in the cerebellum than in the cerebrum in the same mouse at either 6W or 8M of age. C. Alkaline ceramidase activity on NBD-C12-PHC in the brains of young (6W) versus middle-aged mice (8M). Note that the alkaline ceramidase activity was higher in both cerebrum and cerebellum in 8M-old-mice compared to 6W-old mice and that the alkaline ceramidase activity was higher in the cerebellum than in the cerebrum in mice at either age. Data in A, B, and C represent mean values ± SD, n = 3.

Mentions: It has been shown that alkaline ceramidase activity increases with age in the mouse brain [42]. We hypothesized that this ceramidase activity increase may be important in preventing an accumulation of ceramides in the mature brain by catalyzing the hydrolysis of ceramides. To test this possibility, we determined whether inhibiting the increase in ceramidase activity would lead to an aberrant accumulation of ceramides in the brain and consequent neurological disorder. To achieve this goal, we first determined which alkaline ceramidase(s) is upregulated with age in mouse brain. With quantitative real-time polymerase chain reaction (qPCR), we demonstrated that the mRNA levels of Acer3 but not Acer1 or Acer2 were increased in both cerebrum and cerebellum of C57BL6/J wild-type (WT) mice at 8 months of age compared to mice at 6 weeks of age (Fig 1A). We also found that Acer3 mRNA levels were higher in the cerebellum than in the cerebrum (Fig 1B). To determine if the increase in Acer3 mRNA levels results in an increase in its enzymatic activity, we measured alkaline ceramidase activity on NBD-ribo-C12-NBD-phytoceramide (NBD-C12-PHC), a synthetic substrate specific for the human ACER3 [30] and presumably for the mouse Acer3 as well. Our results showed that alkaline ceramidase activity toward NBD-C12-PHC was increased in both the cerebrum and cerebellum in 8-month-old WT mice compared to 6-week-old WT mice (Fig 1C), suggesting that Acer3 activity is indeed increased with age in the mouse brain. Correlating with Acer3 mRNA levels, we found that Acer3 activity was higher in the cerebellum than in the cerebrum (Fig 1C). These results suggest that Acer3 is upregulated with age in both the cerebrum and cerebellum.


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

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 - PLoS Genet. (2015)

Acer3 is upregulated with age in the mouse brain.A. mRNA levels of the alkaline ceramidases Acer1, Acer2, and Acer3 in the cerebra and cerebella of young [6 weeks (6W) of age] versus middle-aged mice [8 months (8M) of age] Note that the mRNA levels of Acer3 but not Acer1 or Acer2 were increased in mice at 8M of age compared to at 6W. B. Acer3 mRNA levels in the cerebellum versus the cerebrum of 6W or 8M-old mice. Note that Acer3 mRNA levels were higher in the cerebellum than in the cerebrum in the same mouse at either 6W or 8M of age. C. Alkaline ceramidase activity on NBD-C12-PHC in the brains of young (6W) versus middle-aged mice (8M). Note that the alkaline ceramidase activity was higher in both cerebrum and cerebellum in 8M-old-mice compared to 6W-old mice and that the alkaline ceramidase activity was higher in the cerebellum than in the cerebrum in mice at either age. Data in A, B, and C represent mean values ± SD, n = 3.
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pgen.1005591.g001: Acer3 is upregulated with age in the mouse brain.A. mRNA levels of the alkaline ceramidases Acer1, Acer2, and Acer3 in the cerebra and cerebella of young [6 weeks (6W) of age] versus middle-aged mice [8 months (8M) of age] Note that the mRNA levels of Acer3 but not Acer1 or Acer2 were increased in mice at 8M of age compared to at 6W. B. Acer3 mRNA levels in the cerebellum versus the cerebrum of 6W or 8M-old mice. Note that Acer3 mRNA levels were higher in the cerebellum than in the cerebrum in the same mouse at either 6W or 8M of age. C. Alkaline ceramidase activity on NBD-C12-PHC in the brains of young (6W) versus middle-aged mice (8M). Note that the alkaline ceramidase activity was higher in both cerebrum and cerebellum in 8M-old-mice compared to 6W-old mice and that the alkaline ceramidase activity was higher in the cerebellum than in the cerebrum in mice at either age. Data in A, B, and C represent mean values ± SD, n = 3.
Mentions: It has been shown that alkaline ceramidase activity increases with age in the mouse brain [42]. We hypothesized that this ceramidase activity increase may be important in preventing an accumulation of ceramides in the mature brain by catalyzing the hydrolysis of ceramides. To test this possibility, we determined whether inhibiting the increase in ceramidase activity would lead to an aberrant accumulation of ceramides in the brain and consequent neurological disorder. To achieve this goal, we first determined which alkaline ceramidase(s) is upregulated with age in mouse brain. With quantitative real-time polymerase chain reaction (qPCR), we demonstrated that the mRNA levels of Acer3 but not Acer1 or Acer2 were increased in both cerebrum and cerebellum of C57BL6/J wild-type (WT) mice at 8 months of age compared to mice at 6 weeks of age (Fig 1A). We also found that Acer3 mRNA levels were higher in the cerebellum than in the cerebrum (Fig 1B). To determine if the increase in Acer3 mRNA levels results in an increase in its enzymatic activity, we measured alkaline ceramidase activity on NBD-ribo-C12-NBD-phytoceramide (NBD-C12-PHC), a synthetic substrate specific for the human ACER3 [30] and presumably for the mouse Acer3 as well. Our results showed that alkaline ceramidase activity toward NBD-C12-PHC was increased in both the cerebrum and cerebellum in 8-month-old WT mice compared to 6-week-old WT mice (Fig 1C), suggesting that Acer3 activity is indeed increased with age in the mouse brain. Correlating with Acer3 mRNA levels, we found that Acer3 activity was higher in the cerebellum than in the cerebrum (Fig 1C). These results suggest that Acer3 is upregulated with age in both the cerebrum and cerebellum.

Bottom Line: However, mechanisms that maintain the homeostasis of these bioactive sphingolipids in the brain remain unclear.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus