title: A deficiency of ceramide biosynthesis causes cerebellar purkinje cell neurodegeneration and lipofuscin accumulation.
abstract: 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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhao
authors.forename: Stefka D
authors.initials: SD
authors.lastname: Spassieva
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jucius
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: H Elizabeth
authors.initials: HE
authors.lastname: Shick
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Macklin
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.forename: Lina M
authors.initials: LM
authors.lastname: Obeid
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ackerman
mesh_terms: D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002454:Cell Differentiation; D002518:Ceramides / Q000096:biosynthesis* / Q000172:deficiency; D002522:Chlorocebus aethiops; D006706:Homeostasis; D008062:Lipofuscin / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism*; D051049:Sphingosine N-Acyltransferase / Q000235:genetics / Q000378:metabolism
chemical_list: D002518:Ceramides; D008062:Lipofuscin; D008565:Membrane Proteins; C000609885:CerS1 protein, mouse; D051049:Sphingosine N-Acyltransferase