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 knockout does not affect myelination.A-D. Cerebellar sections of Acer3+/+ and Acer3-/- mice at 8M of age were stained with Luxol fast blue (A). The myelin width indicated by black arrowhead was measured in the images of the cerebellar sections stained with Luxol fast blue (B). MBP protein levels in cerebellar homogenates were analyzed by immunoblotting (C) and quantified (D). E. Electron microscopy of the ultrastructure of myelin sheaths in the cerebellum of Acer3+/+ and Acer3-/- mice at 8M of age. The image in A or E represents the results from one of four mice in each group. The data in B and D represent mean values ± SD, n = 4.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1005591.g010: Acer3 knockout does not affect myelination.A-D. Cerebellar sections of Acer3+/+ and Acer3-/- mice at 8M of age were stained with Luxol fast blue (A). The myelin width indicated by black arrowhead was measured in the images of the cerebellar sections stained with Luxol fast blue (B). MBP protein levels in cerebellar homogenates were analyzed by immunoblotting (C) and quantified (D). E. Electron microscopy of the ultrastructure of myelin sheaths in the cerebellum of Acer3+/+ and Acer3-/- mice at 8M of age. The image in A or E represents the results from one of four mice in each group. The data in B and D represent mean values ± SD, n = 4.

Mentions: Because dyshomeostasis of sphingolipids could lead to a defect in myelination, which has been linked to various neurological disorders including cerebellar ataxia [48,49], we tested if Acer3 deficiency impaired myelination in the cerebellum in mice at 8 months of age. Luxol fast blue staining showed that the width of myelinated tracts was not altered in Acer3-/- mice as compared to Acer3+/+ mice (Fig 10A and 10B). Consistently, Western blot analyses found no difference in the levels of myelin basic protein (MBP) in the cerebellum between Acer3+/+ and Acer3-/- mice (Fig 10C and 10D). Electron microscopy revealed that Acer3 deficiency did not alter the ultrastructure of myelin sheaths in the cerebellum (Fig 10E). These results suggest that Acer3 deficiency does not affect myelination.


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 knockout does not affect myelination.A-D. Cerebellar sections of Acer3+/+ and Acer3-/- mice at 8M of age were stained with Luxol fast blue (A). The myelin width indicated by black arrowhead was measured in the images of the cerebellar sections stained with Luxol fast blue (B). MBP protein levels in cerebellar homogenates were analyzed by immunoblotting (C) and quantified (D). E. Electron microscopy of the ultrastructure of myelin sheaths in the cerebellum of Acer3+/+ and Acer3-/- mice at 8M of age. The image in A or E represents the results from one of four mice in each group. The data in B and D represent mean values ± SD, n = 4.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1005591.g010: Acer3 knockout does not affect myelination.A-D. Cerebellar sections of Acer3+/+ and Acer3-/- mice at 8M of age were stained with Luxol fast blue (A). The myelin width indicated by black arrowhead was measured in the images of the cerebellar sections stained with Luxol fast blue (B). MBP protein levels in cerebellar homogenates were analyzed by immunoblotting (C) and quantified (D). E. Electron microscopy of the ultrastructure of myelin sheaths in the cerebellum of Acer3+/+ and Acer3-/- mice at 8M of age. The image in A or E represents the results from one of four mice in each group. The data in B and D represent mean values ± SD, n = 4.
Mentions: Because dyshomeostasis of sphingolipids could lead to a defect in myelination, which has been linked to various neurological disorders including cerebellar ataxia [48,49], we tested if Acer3 deficiency impaired myelination in the cerebellum in mice at 8 months of age. Luxol fast blue staining showed that the width of myelinated tracts was not altered in Acer3-/- mice as compared to Acer3+/+ mice (Fig 10A and 10B). Consistently, Western blot analyses found no difference in the levels of myelin basic protein (MBP) in the cerebellum between Acer3+/+ and Acer3-/- mice (Fig 10C and 10D). Electron microscopy revealed that Acer3 deficiency did not alter the ultrastructure of myelin sheaths in the cerebellum (Fig 10E). These results suggest that Acer3 deficiency does not affect myelination.

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