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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 impairs motor coordination and balance capabilities in mice.A-D. Rotarod tests for motor coordination. Acer3+/+ and Acer3-/- mice at 6W, 4M, 6M, 8M, or 12M of age were subjected to rotarod tests under 3 task difficulties—10, 15, and 20 rpm, respectively. Hindlimb step patterns in a representative Acer3+/+ and Acer3-/- mouse at 8M of age at 20 rpm are displayed in D. Note that the hindpaws of Acer3-/- mice, but not those of Acer3+/+ mice slipped off the rod. E-H. Beam walking tests for motor coordination and balance capabilities. Acer3+/+ and Acer3-/- mice at 6W or 8M of age were subjected to beam walking tests under two task difficulties. The average of three trials were quantitatively analyzed for time to traverse the beam (E), walking distance (F), and foot-slips of hindpaws (G). Patterns of hindpaw contacting the beam during walking in a representative 8-month-old Acer3+/+ and Acer3-/- mouse are displayed in H. Note the foot-slips for both beam walking conditions in the Acer3-/- mouse. The data in A, B, C, E, F, and G represent mean values ± SD, n = 5–8. n.s., not significant.
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pgen.1005591.g007: Acer3 knockout impairs motor coordination and balance capabilities in mice.A-D. Rotarod tests for motor coordination. Acer3+/+ and Acer3-/- mice at 6W, 4M, 6M, 8M, or 12M of age were subjected to rotarod tests under 3 task difficulties—10, 15, and 20 rpm, respectively. Hindlimb step patterns in a representative Acer3+/+ and Acer3-/- mouse at 8M of age at 20 rpm are displayed in D. Note that the hindpaws of Acer3-/- mice, but not those of Acer3+/+ mice slipped off the rod. E-H. Beam walking tests for motor coordination and balance capabilities. Acer3+/+ and Acer3-/- mice at 6W or 8M of age were subjected to beam walking tests under two task difficulties. The average of three trials were quantitatively analyzed for time to traverse the beam (E), walking distance (F), and foot-slips of hindpaws (G). Patterns of hindpaw contacting the beam during walking in a representative 8-month-old Acer3+/+ and Acer3-/- mouse are displayed in H. Note the foot-slips for both beam walking conditions in the Acer3-/- mouse. The data in A, B, C, E, F, and G represent mean values ± SD, n = 5–8. n.s., not significant.

Mentions: We then performed rotarod tests to assess general motor coordination and balance. These tests were carried out with three task difficulties by varying the speed, and the latency to fall off the rod was recorded. We found that Acer3-/- mice did not exhibit any significant difference in the latency to fall prior to 6 months of age when compared to its age-matched WT littermates (Fig 7A–7C). However, starting from 8 months of age, Acer3-/- mice had difficulty staying on the rotarod at all testing speeds—walking on the rod was characterized by frequent bilateral foot-slips, decline in bilateral alternating movement patterns between the forelimb and hindlimbs and lack of balance, all of which led the Acer3-/- mice to fall off the rod within a very short period. This was in striking contrast to the age-matched WT littermates who demonstrated significantly longer durations of walking times on the rotarod at all speed settings (Fig 7A–7D, S2 Video).


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 impairs motor coordination and balance capabilities in mice.A-D. Rotarod tests for motor coordination. Acer3+/+ and Acer3-/- mice at 6W, 4M, 6M, 8M, or 12M of age were subjected to rotarod tests under 3 task difficulties—10, 15, and 20 rpm, respectively. Hindlimb step patterns in a representative Acer3+/+ and Acer3-/- mouse at 8M of age at 20 rpm are displayed in D. Note that the hindpaws of Acer3-/- mice, but not those of Acer3+/+ mice slipped off the rod. E-H. Beam walking tests for motor coordination and balance capabilities. Acer3+/+ and Acer3-/- mice at 6W or 8M of age were subjected to beam walking tests under two task difficulties. The average of three trials were quantitatively analyzed for time to traverse the beam (E), walking distance (F), and foot-slips of hindpaws (G). Patterns of hindpaw contacting the beam during walking in a representative 8-month-old Acer3+/+ and Acer3-/- mouse are displayed in H. Note the foot-slips for both beam walking conditions in the Acer3-/- mouse. The data in A, B, C, E, F, and G represent mean values ± SD, n = 5–8. n.s., not significant.
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pgen.1005591.g007: Acer3 knockout impairs motor coordination and balance capabilities in mice.A-D. Rotarod tests for motor coordination. Acer3+/+ and Acer3-/- mice at 6W, 4M, 6M, 8M, or 12M of age were subjected to rotarod tests under 3 task difficulties—10, 15, and 20 rpm, respectively. Hindlimb step patterns in a representative Acer3+/+ and Acer3-/- mouse at 8M of age at 20 rpm are displayed in D. Note that the hindpaws of Acer3-/- mice, but not those of Acer3+/+ mice slipped off the rod. E-H. Beam walking tests for motor coordination and balance capabilities. Acer3+/+ and Acer3-/- mice at 6W or 8M of age were subjected to beam walking tests under two task difficulties. The average of three trials were quantitatively analyzed for time to traverse the beam (E), walking distance (F), and foot-slips of hindpaws (G). Patterns of hindpaw contacting the beam during walking in a representative 8-month-old Acer3+/+ and Acer3-/- mouse are displayed in H. Note the foot-slips for both beam walking conditions in the Acer3-/- mouse. The data in A, B, C, E, F, and G represent mean values ± SD, n = 5–8. n.s., not significant.
Mentions: We then performed rotarod tests to assess general motor coordination and balance. These tests were carried out with three task difficulties by varying the speed, and the latency to fall off the rod was recorded. We found that Acer3-/- mice did not exhibit any significant difference in the latency to fall prior to 6 months of age when compared to its age-matched WT littermates (Fig 7A–7C). However, starting from 8 months of age, Acer3-/- mice had difficulty staying on the rotarod at all testing speeds—walking on the rod was characterized by frequent bilateral foot-slips, decline in bilateral alternating movement patterns between the forelimb and hindlimbs and lack of balance, all of which led the Acer3-/- mice to fall off the rod within a very short period. This was in striking contrast to the age-matched WT littermates who demonstrated significantly longer durations of walking times on the rotarod at all speed settings (Fig 7A–7D, S2 Video).

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