- Published: May 19, 2011
- DOI: 10.1371/journal.pgen.1002063
. 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
- Official Symbol CERS1provided by HGNC
- Official Full Name ceramide synthase 1provided by HGNC
- Primary source HGNC:HGNC:14253
- See related Ensembl:ENSG00000223802; HPRD:12114; MIM:606919; Vega:OTTHUMG00000183049
- Gene type protein coding
- RefSeq status REVIEWED
- Organism Homo sapiens
- Lineage Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
- Also known as EPM8; LAG1; UOG1; LASS1
- Summary This gene encodes a member of the bone morphogenetic protein (BMP) family and the TGF-beta superfamily. This group of proteins is characterized by a polybasic proteolytic processing site that is cleaved to produce a mature protein containing seven conserved cysteine residues. Members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Studies in yeast suggest that the encoded protein is involved in aging. This protein is transcribed from a monocistronic mRNA as well as a bicistronic mRNA, which also encodes growth differentiation factor 1. [provided by RefSeq, Jul 2008] Orthologsmouse all
ORIGIN 1 maaagpaagp tgpepmpsya qlvqrgwgsa laaargctdc gwglarrgla ehahlappel 61 lllalgalgw talrsaatar lfrplakrcc lqprdaakmp esawkflfyl gswsysayll 121 fgtdypffhd ppsvfydwtp gmavprdiaa ayllqgsfyg hsiyatlymd twrkdsvvml 181 lhhvvtlili vssyafryhn vgilvlflhd isdvqleftk lniyfksrgg syhrlhalaa 241 dlgclsfgfs wfwfrlywfp lkvlyatshc slrtvpdipf yfffnallll ltlmnlywfl 301 yivafaakvl tgqvhelkdl reydtaeaqs lkpskaekpl rnglvkdkrf