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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 knockout decreases alkaline ceramidase activity on ULCC in the brain.A. The transcription of a truncated coding sequence in a representative Acer3 knockout mouse. RNAs were isolated from the brains of Acer3+/+ or Acer3-/- mice and subjected to RT-PCR using a pair of primers encompassing the start codon and stop codon, respectively, of the Acer3 gene. Note that the Acer3-/- mouse has a smaller ORF of the Acer3 gene than an age-matched Acer3+/+ mouse. B. Reduction of alkaline ceramidase activity on NBD-C12-PHC in Acer3-/- mice. Note that Acer3-/- mice at either 6W or 8M of age show significant declines in ceramidase activity in both the cerebellar and cerebral brains compared to their WT littermates. C. Reduction of alkaline ceramidase activity on C18:1-ceramide in the whole brains of Acer3 knockout mice. Note that the brain alkaline ceramidase activity on this ceramide was substantially decreased in Acer3-/- mice compared to Acer3+/+ mice. Image in A represents result from 3 pairs of mice. Data in B and C represent mean values ± SD, n = 3.
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pgen.1005591.g004: Acer3 knockout decreases alkaline ceramidase activity on ULCC in the brain.A. The transcription of a truncated coding sequence in a representative Acer3 knockout mouse. RNAs were isolated from the brains of Acer3+/+ or Acer3-/- mice and subjected to RT-PCR using a pair of primers encompassing the start codon and stop codon, respectively, of the Acer3 gene. Note that the Acer3-/- mouse has a smaller ORF of the Acer3 gene than an age-matched Acer3+/+ mouse. B. Reduction of alkaline ceramidase activity on NBD-C12-PHC in Acer3-/- mice. Note that Acer3-/- mice at either 6W or 8M of age show significant declines in ceramidase activity in both the cerebellar and cerebral brains compared to their WT littermates. C. Reduction of alkaline ceramidase activity on C18:1-ceramide in the whole brains of Acer3 knockout mice. Note that the brain alkaline ceramidase activity on this ceramide was substantially decreased in Acer3-/- mice compared to Acer3+/+ mice. Image in A represents result from 3 pairs of mice. Data in B and C represent mean values ± SD, n = 3.

Mentions: To confirm that the deletion of exon 8 of the Acer3 gene indeed results in a truncated coding sequence of Acer3, we amplified the coding sequence from cDNAs that are transcribed from RNAs from brain tissues of Acer3+/+ or Acer3-/- mice. With reverse transcription PCR (RT-PCR), we demonstrated that the coding sequence of Acer3 in Acer3-/- mice is shorter in length than that in Acer3+/+ mice (Fig 4A), suggesting that a truncated coding sequence is transcribed in Acer3-/- mice.


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 decreases alkaline ceramidase activity on ULCC in the brain.A. The transcription of a truncated coding sequence in a representative Acer3 knockout mouse. RNAs were isolated from the brains of Acer3+/+ or Acer3-/- mice and subjected to RT-PCR using a pair of primers encompassing the start codon and stop codon, respectively, of the Acer3 gene. Note that the Acer3-/- mouse has a smaller ORF of the Acer3 gene than an age-matched Acer3+/+ mouse. B. Reduction of alkaline ceramidase activity on NBD-C12-PHC in Acer3-/- mice. Note that Acer3-/- mice at either 6W or 8M of age show significant declines in ceramidase activity in both the cerebellar and cerebral brains compared to their WT littermates. C. Reduction of alkaline ceramidase activity on C18:1-ceramide in the whole brains of Acer3 knockout mice. Note that the brain alkaline ceramidase activity on this ceramide was substantially decreased in Acer3-/- mice compared to Acer3+/+ mice. Image in A represents result from 3 pairs of mice. Data in B and C represent mean values ± SD, n = 3.
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Related In: Results  -  Collection

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pgen.1005591.g004: Acer3 knockout decreases alkaline ceramidase activity on ULCC in the brain.A. The transcription of a truncated coding sequence in a representative Acer3 knockout mouse. RNAs were isolated from the brains of Acer3+/+ or Acer3-/- mice and subjected to RT-PCR using a pair of primers encompassing the start codon and stop codon, respectively, of the Acer3 gene. Note that the Acer3-/- mouse has a smaller ORF of the Acer3 gene than an age-matched Acer3+/+ mouse. B. Reduction of alkaline ceramidase activity on NBD-C12-PHC in Acer3-/- mice. Note that Acer3-/- mice at either 6W or 8M of age show significant declines in ceramidase activity in both the cerebellar and cerebral brains compared to their WT littermates. C. Reduction of alkaline ceramidase activity on C18:1-ceramide in the whole brains of Acer3 knockout mice. Note that the brain alkaline ceramidase activity on this ceramide was substantially decreased in Acer3-/- mice compared to Acer3+/+ mice. Image in A represents result from 3 pairs of mice. Data in B and C represent mean values ± SD, n = 3.
Mentions: To confirm that the deletion of exon 8 of the Acer3 gene indeed results in a truncated coding sequence of Acer3, we amplified the coding sequence from cDNAs that are transcribed from RNAs from brain tissues of Acer3+/+ or Acer3-/- mice. With reverse transcription PCR (RT-PCR), we demonstrated that the coding sequence of Acer3 in Acer3-/- mice is shorter in length than that in Acer3+/+ mice (Fig 4A), suggesting that a truncated coding sequence is transcribed in Acer3-/- mice.

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