Limits...
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 ceramides, SPH, and S1P in aging brain.A-B. Levels of individual ceramide species and total levels of ceramides in the cerebrum (A) and cerebellum (B) of Acer3-/- or Acer3+/+ mice at 8M or 6W of age. Note that C18:1-ceramide was significantly decreased in both the cerebrum and cerebellum of 8M-old Acer3+/+ mice compared to 6W-old Acer3+/+ mice and that this decrease was reverted in Acer3-/- mice. C. SPH and S1P levels in the cerebrum and cerebellum in Acer3+/+ or Acer3-/- mice at 6W or 8M of age. Note that both SPH and S1P levels were increased in both the cerebrum and cerebellum in Acer3+/+ mice at 8M of age compared to at 6M-old of age and that these age-dependent increases in SPH and S1P were reverted in Acer3-/- mice. Total levels of sphingolipids were the sum of individual species of the same class. Data in A-C represent mean values ± SD, n = 3.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4608763&req=5

pgen.1005591.g005: Acer3 upregulation is important for the homeostasis of ceramides, SPH, and S1P in aging brain.A-B. Levels of individual ceramide species and total levels of ceramides in the cerebrum (A) and cerebellum (B) of Acer3-/- or Acer3+/+ mice at 8M or 6W of age. Note that C18:1-ceramide was significantly decreased in both the cerebrum and cerebellum of 8M-old Acer3+/+ mice compared to 6W-old Acer3+/+ mice and that this decrease was reverted in Acer3-/- mice. C. SPH and S1P levels in the cerebrum and cerebellum in Acer3+/+ or Acer3-/- mice at 6W or 8M of age. Note that both SPH and S1P levels were increased in both the cerebrum and cerebellum in Acer3+/+ mice at 8M of age compared to at 6M-old of age and that these age-dependent increases in SPH and S1P were reverted in Acer3-/- mice. Total levels of sphingolipids were the sum of individual species of the same class. Data in A-C represent mean values ± SD, n = 3.

Mentions: To investigate if Acer3 plays a role in regulating the homeostasis of ceramides and their sphingolipid derivatives in the brain during aging, we first measured the levels of ceramides in cerebral and cerebellar tissues from Acer3+/+ and Acer3-/- mice at 6 weeks and 8 months of age using LC-MS/MS. In mice at 6 weeks of age, Acer3 knockout increased not only the levels of ULCCs (C18:1 and C20:1-ceramides) but also the levels of saturated LCCs (SLCCs; C16:0, C18:0, and/or C20:0-ceramides) in the cerebrum (Fig 5A), and to a greater extent in the cerebellum (Fig 5B). Acer3 deficiency increased the total levels of ceramides in the cerebellum (Fig 5B) and to a lesser extent in the cerebrum (Fig 5A) in 6-week-old mice. In mice at 8 months of age, Acer3 knockout further accumulated ULCCs and SLCCs in both the cerebrum and the cerebellum, while there was an accumulation of VLCCs (C22 and C22:1-ceramide) only in the cerebellum. The total levels of ceramides were therefore elevated in both brain regions, but were greater in the cerebellum (Fig 5A and 5B). It is worth noting that parallel to the upregulation of Acer3 in the brain, the levels of C18:1-ceramide were decreased in both the cerebrum and cerebellum in 8-month-old mice compared to 6-week-old wild-type mice. Importantly, this decrease was inhibited by Acer3 knockout, suggesting that Acer3 upregulation is important in prohibiting the aberrant accumulation of C18:1-ceramide in the aging brain.


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 ceramides, SPH, and S1P in aging brain.A-B. Levels of individual ceramide species and total levels of ceramides in the cerebrum (A) and cerebellum (B) of Acer3-/- or Acer3+/+ mice at 8M or 6W of age. Note that C18:1-ceramide was significantly decreased in both the cerebrum and cerebellum of 8M-old Acer3+/+ mice compared to 6W-old Acer3+/+ mice and that this decrease was reverted in Acer3-/- mice. C. SPH and S1P levels in the cerebrum and cerebellum in Acer3+/+ or Acer3-/- mice at 6W or 8M of age. Note that both SPH and S1P levels were increased in both the cerebrum and cerebellum in Acer3+/+ mice at 8M of age compared to at 6M-old of age and that these age-dependent increases in SPH and S1P were reverted in Acer3-/- mice. Total levels of sphingolipids were the sum of individual species of the same class. Data in A-C represent mean values ± SD, n = 3.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608763&req=5

pgen.1005591.g005: Acer3 upregulation is important for the homeostasis of ceramides, SPH, and S1P in aging brain.A-B. Levels of individual ceramide species and total levels of ceramides in the cerebrum (A) and cerebellum (B) of Acer3-/- or Acer3+/+ mice at 8M or 6W of age. Note that C18:1-ceramide was significantly decreased in both the cerebrum and cerebellum of 8M-old Acer3+/+ mice compared to 6W-old Acer3+/+ mice and that this decrease was reverted in Acer3-/- mice. C. SPH and S1P levels in the cerebrum and cerebellum in Acer3+/+ or Acer3-/- mice at 6W or 8M of age. Note that both SPH and S1P levels were increased in both the cerebrum and cerebellum in Acer3+/+ mice at 8M of age compared to at 6M-old of age and that these age-dependent increases in SPH and S1P were reverted in Acer3-/- mice. Total levels of sphingolipids were the sum of individual species of the same class. Data in A-C represent mean values ± SD, n = 3.
Mentions: To investigate if Acer3 plays a role in regulating the homeostasis of ceramides and their sphingolipid derivatives in the brain during aging, we first measured the levels of ceramides in cerebral and cerebellar tissues from Acer3+/+ and Acer3-/- mice at 6 weeks and 8 months of age using LC-MS/MS. In mice at 6 weeks of age, Acer3 knockout increased not only the levels of ULCCs (C18:1 and C20:1-ceramides) but also the levels of saturated LCCs (SLCCs; C16:0, C18:0, and/or C20:0-ceramides) in the cerebrum (Fig 5A), and to a greater extent in the cerebellum (Fig 5B). Acer3 deficiency increased the total levels of ceramides in the cerebellum (Fig 5B) and to a lesser extent in the cerebrum (Fig 5A) in 6-week-old mice. In mice at 8 months of age, Acer3 knockout further accumulated ULCCs and SLCCs in both the cerebrum and the cerebellum, while there was an accumulation of VLCCs (C22 and C22:1-ceramide) only in the cerebellum. The total levels of ceramides were therefore elevated in both brain regions, but were greater in the cerebellum (Fig 5A and 5B). It is worth noting that parallel to the upregulation of Acer3 in the brain, the levels of C18:1-ceramide were decreased in both the cerebrum and cerebellum in 8-month-old mice compared to 6-week-old wild-type mice. Importantly, this decrease was inhibited by Acer3 knockout, suggesting that Acer3 upregulation is important in prohibiting the aberrant accumulation of C18:1-ceramide in the aging brain.

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