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måndag 1 juni 2015

Keramidin bosynteesi : Keramidisyntaasin puute


Research Article
A Deficiency of Ceramide Biosynthesis Causes Cerebellar Purkinje Cell Neurodegeneration and Lipofuscin Accumulation
Lihong Zhao, Stefka D. Spassieva, et al.
  • Published: May 19, 2011
  • DOI: 10.1371/journal.pgen.1002063
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

GEENI Kr19p12
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 
        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

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