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

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.
Author Summary Lipids play many essential cellular roles as structural components of biological membranes or signaling molecules. Alterations of lipids have been observed in the brains of patients with neurodegenerative diseases. However, whether these changes can cause neurodegeneration or otherwise influence the pathology of these diseases is unclear. We identified mouse mutations in a gene encoding a neuronally expressed enzyme that generates ceramide, the basic structural component of many lipids known as sphingolipids. These mutations result in progressive ataxia and loss of cerebellar Purkinje cells. In addition, many neurons in these mutant mice harbor lipofuscin, a storage material containing both membranes and proteins, that is present in aging brains and in brains of patients with neurodegenerative disorders, suggesting that both membrane and protein homeostasis are impaired in mutant neurons. This study directly demonstrates that disruption of sphingolipid biosynthesis can lead to selective neuron death and the abnormal accumulation of lipofuscin, and it underscores the need for further study of the roles of lipids in neurodegenerative disorders.