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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 upregulation is important for the homeostasis of complex sphingolipid in aging brain.A and B. Levels of individual monohexosylceramide (HexCer) species and levels of total HexCers in the cerebrum (A) and cerebellum (B) of Acer3+/+ or Acer3-/- mice at 8M or 6W of age. Note that although causing a several-fold increase in the levels of C18:1-HexCer in both the cerebrum and cerebellum in mice at either age, Acer3 knockout did not alter the total levels of HexCers. C and D. Levels of individual sphingomyelins and total levels of ceramides in the cerebrum (C) and cerebellum (D) of Acer3+/+ or Acer3-/- mice at 6W or 8Mof age. Note that Acer3 knockout only slightly increased the levels of C18:1 or C20:1-sphingomyelin in the cerebellum but not cerebrum in mice at either age without affecting the total levels of sphingomyelins in either brain region at either age. Total levels of sphingolipids were the sum of individual species of the same class. Data in A-D represent mean values ± SD, n = 3.
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pgen.1005591.g006: Acer3 upregulation is important for the homeostasis of complex sphingolipid in aging brain.A and B. Levels of individual monohexosylceramide (HexCer) species and levels of total HexCers in the cerebrum (A) and cerebellum (B) of Acer3+/+ or Acer3-/- mice at 8M or 6W of age. Note that although causing a several-fold increase in the levels of C18:1-HexCer in both the cerebrum and cerebellum in mice at either age, Acer3 knockout did not alter the total levels of HexCers. C and D. Levels of individual sphingomyelins and total levels of ceramides in the cerebrum (C) and cerebellum (D) of Acer3+/+ or Acer3-/- mice at 6W or 8Mof age. Note that Acer3 knockout only slightly increased the levels of C18:1 or C20:1-sphingomyelin in the cerebellum but not cerebrum in mice at either age without affecting the total levels of sphingomyelins in either brain region at either age. Total levels of sphingolipids were the sum of individual species of the same class. Data in A-D represent mean values ± SD, n = 3.

Mentions: Ceramides can be incorporated into various complex sphingolipids. Since we observed an increase in the levels of brain ceramides in Acer3-/- mice, we postulated that Acer3 deficiency may increase the levels of complex sphingolipids in the brain. To investigate this possibility, the levels of monohexosylceramides (HexCers) and sphingomyelins were determined in the cerebrum and cerebellum in Acer3+/+ and Acer3-/- mice using LC-MS/MS. Acer3 knockout increased the levels of C18:1-HexCer, a very minor HexCer species, in the cerebrum (Fig 6A) and cerebellum (Fig 6B) in 6-week-old mice and to a greater extent in 8-month-old mice without affecting the levels of other HexCer species or total levels of HexCers (Fig 6A and 6B). These results suggest that Acer3 regulates brain C18:1-HexCer specifically and that its deficiency does not affect the total levels of this type of sphingolipids. As for sphingomyelins, the results showed that Acer3 knockout slightly but significantly increased the levels of C18:1 and C20:1-sphingomyelin in the cerebellum in mice at either 6 weeks or 8 months of age without affecting the total levels of sphingomyelins in this tissue and this effect was not observed in the cerebrum (Fig 6C and 6D). These results suggest that Acer3 regulates unsaturated long-chain sphingomyelins specially and that its deficiency does not affect the total levels of sphingomyelins.


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 upregulation is important for the homeostasis of complex sphingolipid in aging brain.A and B. Levels of individual monohexosylceramide (HexCer) species and levels of total HexCers in the cerebrum (A) and cerebellum (B) of Acer3+/+ or Acer3-/- mice at 8M or 6W of age. Note that although causing a several-fold increase in the levels of C18:1-HexCer in both the cerebrum and cerebellum in mice at either age, Acer3 knockout did not alter the total levels of HexCers. C and D. Levels of individual sphingomyelins and total levels of ceramides in the cerebrum (C) and cerebellum (D) of Acer3+/+ or Acer3-/- mice at 6W or 8Mof age. Note that Acer3 knockout only slightly increased the levels of C18:1 or C20:1-sphingomyelin in the cerebellum but not cerebrum in mice at either age without affecting the total levels of sphingomyelins in either brain region at either age. Total levels of sphingolipids were the sum of individual species of the same class. Data in A-D represent mean values ± SD, n = 3.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4608763&req=5

pgen.1005591.g006: Acer3 upregulation is important for the homeostasis of complex sphingolipid in aging brain.A and B. Levels of individual monohexosylceramide (HexCer) species and levels of total HexCers in the cerebrum (A) and cerebellum (B) of Acer3+/+ or Acer3-/- mice at 8M or 6W of age. Note that although causing a several-fold increase in the levels of C18:1-HexCer in both the cerebrum and cerebellum in mice at either age, Acer3 knockout did not alter the total levels of HexCers. C and D. Levels of individual sphingomyelins and total levels of ceramides in the cerebrum (C) and cerebellum (D) of Acer3+/+ or Acer3-/- mice at 6W or 8Mof age. Note that Acer3 knockout only slightly increased the levels of C18:1 or C20:1-sphingomyelin in the cerebellum but not cerebrum in mice at either age without affecting the total levels of sphingomyelins in either brain region at either age. Total levels of sphingolipids were the sum of individual species of the same class. Data in A-D represent mean values ± SD, n = 3.
Mentions: Ceramides can be incorporated into various complex sphingolipids. Since we observed an increase in the levels of brain ceramides in Acer3-/- mice, we postulated that Acer3 deficiency may increase the levels of complex sphingolipids in the brain. To investigate this possibility, the levels of monohexosylceramides (HexCers) and sphingomyelins were determined in the cerebrum and cerebellum in Acer3+/+ and Acer3-/- mice using LC-MS/MS. Acer3 knockout increased the levels of C18:1-HexCer, a very minor HexCer species, in the cerebrum (Fig 6A) and cerebellum (Fig 6B) in 6-week-old mice and to a greater extent in 8-month-old mice without affecting the levels of other HexCer species or total levels of HexCers (Fig 6A and 6B). These results suggest that Acer3 regulates brain C18:1-HexCer specifically and that its deficiency does not affect the total levels of this type of sphingolipids. As for sphingomyelins, the results showed that Acer3 knockout slightly but significantly increased the levels of C18:1 and C20:1-sphingomyelin in the cerebellum in mice at either 6 weeks or 8 months of age without affecting the total levels of sphingomyelins in this tissue and this effect was not observed in the cerebrum (Fig 6C and 6D). These results suggest that Acer3 regulates unsaturated long-chain sphingomyelins specially and that its deficiency does not affect the total levels of sphingomyelins.

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