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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 induces hindlimb clasping phenotype in mice.A and B. Hindlimb clasping reflex tests. Hindlimb clasping reflex was scored in Acer3+/+ and Acer3-/- mice at 6W, 4M, 6M, 8M, and 12M of age (A). At 8M of age, Acer3+/+ splayed their hindlimbs outward and away from the abdomen similar to what was seen in the 6W mice, whereas Acer3-/- mice retracted their hindlimbs toward the abdomen into a clasping reflex (B). The data in A represent mean values ± SD, n = 5–8. n.s., not significant.
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pgen.1005591.g008: Acer3 knockout induces hindlimb clasping phenotype in mice.A and B. Hindlimb clasping reflex tests. Hindlimb clasping reflex was scored in Acer3+/+ and Acer3-/- mice at 6W, 4M, 6M, 8M, and 12M of age (A). At 8M of age, Acer3+/+ splayed their hindlimbs outward and away from the abdomen similar to what was seen in the 6W mice, whereas Acer3-/- mice retracted their hindlimbs toward the abdomen into a clasping reflex (B). The data in A represent mean values ± SD, n = 5–8. n.s., not significant.

Mentions: Finally, the hindlimb clasping reflex was tested to determine if Acer3-/- mice exhibit any neuropathology. Acer3+/+ and Acer3-/- mice were suspended by the base of the tail for 10 s, and the duration of hindlimb clasping was scored. At 6 weeks to 6 months of age, both Acer3+/+ and Acer3-/- knockout mice splayed their hindlimbs outward and away from the abdomen with no clasping reflex (Fig 8A). Starting at 8 months of age, while Acer3+/+ mice exhibited the same hindlimb action with no clasping reflex as the 6-week-old mice, Acer3-/- mice retracted their hindlimbs toward the abdomen with a significantly higher hindlimb clasping reflex score than Acer3+/+ mice (Fig 8A and 8B).


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 induces hindlimb clasping phenotype in mice.A and B. Hindlimb clasping reflex tests. Hindlimb clasping reflex was scored in Acer3+/+ and Acer3-/- mice at 6W, 4M, 6M, 8M, and 12M of age (A). At 8M of age, Acer3+/+ splayed their hindlimbs outward and away from the abdomen similar to what was seen in the 6W mice, whereas Acer3-/- mice retracted their hindlimbs toward the abdomen into a clasping reflex (B). The data in A represent mean values ± SD, n = 5–8. n.s., not significant.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4608763&req=5

pgen.1005591.g008: Acer3 knockout induces hindlimb clasping phenotype in mice.A and B. Hindlimb clasping reflex tests. Hindlimb clasping reflex was scored in Acer3+/+ and Acer3-/- mice at 6W, 4M, 6M, 8M, and 12M of age (A). At 8M of age, Acer3+/+ splayed their hindlimbs outward and away from the abdomen similar to what was seen in the 6W mice, whereas Acer3-/- mice retracted their hindlimbs toward the abdomen into a clasping reflex (B). The data in A represent mean values ± SD, n = 5–8. n.s., not significant.
Mentions: Finally, the hindlimb clasping reflex was tested to determine if Acer3-/- mice exhibit any neuropathology. Acer3+/+ and Acer3-/- mice were suspended by the base of the tail for 10 s, and the duration of hindlimb clasping was scored. At 6 weeks to 6 months of age, both Acer3+/+ and Acer3-/- knockout mice splayed their hindlimbs outward and away from the abdomen with no clasping reflex (Fig 8A). Starting at 8 months of age, while Acer3+/+ mice exhibited the same hindlimb action with no clasping reflex as the 6-week-old mice, Acer3-/- mice retracted their hindlimbs toward the abdomen with a significantly higher hindlimb clasping reflex score than Acer3+/+ mice (Fig 8A and 8B).

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