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A deficiency of ceramide biosynthesis causes cerebellar purkinje cell neurodegeneration and lipofuscin accumulation.

PLoS genetics | 2011

Sphingolipids, lipids with a common sphingoid base (also termed long chain base) backbone, play essential cellular structural and signaling functions. Alterations of sphingolipid levels have been implicated in many diseases, including neurodegenerative disorders. However, it remains largely unclear whether sphingolipid changes in these diseases are pathological events or homeostatic responses. Furthermore, how changes in sphingolipid homeostasis shape the progression of aging and neurodegeneration remains to be clarified. We identified two mouse strains, flincher (fln) and toppler (to), with spontaneous recessive mutations that cause cerebellar ataxia and Purkinje cell degeneration. Positional cloning demonstrated that these mutations reside in the Lass1 gene. Lass1 encodes (dihydro)ceramide synthase 1 (CerS1), which is highly expressed in neurons. Both fln and to mutations caused complete loss of CerS1 catalytic activity, which resulted in a reduction in sphingolipid biosynthesis in the brain and dramatic changes in steady-state levels of sphingolipids and sphingoid bases. In addition to Purkinje cell death, deficiency of CerS1 function also induced accumulation of lipofuscin with ubiquitylated proteins in many brain regions. Our results demonstrate clearly that ceramide biosynthesis deficiency can cause neurodegeneration and suggest a novel mechanism of lipofuscin formation, a common phenomenon that occurs during normal aging and in some neurodegenerative diseases.

Pubmed ID: 21625621 RIS Download

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Associated grants

  • Agency: NCI NIH HHS, United States
    Id: P30 CA034196
  • Agency: NCI NIH HHS, United States
    Id: CA34196
  • Agency: BLRD VA, United States
    Id: I01 BX000156
  • Agency: NCRR NIH HHS, United States
    Id: P20 RR017677
  • Agency: NIA NIH HHS, United States
    Id: R01 AG016583

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C57BL/6J (tool)

RRID:IMSR_JAX:000664

Mus musculus with name C57BL/6J from IMSR.

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COS-7 (tool)

RRID:CVCL_0224

Cell line COS-7 is a Transformed cell line with a species of origin Chlorocebus aethiops (Green monkey)

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BALB/cByJ (tool)

RRID:IMSR_JAX:001026

Mus musculus with name BALB/cByJ from IMSR.

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FVB/NJ (tool)

RRID:IMSR_JAX:001800

Mus musculus with name FVB/NJ from IMSR.

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