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Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration
- Source :
- Proceedings of the National Academy of Sciences. 112:12962-12967
- Publication Year :
- 2015
- Publisher :
- Proceedings of the National Academy of Sciences, 2015.
-
Abstract
- Sphingolipids typically have an 18-carbon (C18) sphingoid long chain base (LCB) backbone. Although sphingolipids with LCBs of other chain lengths have been identified, the functional significance of these low-abundance sphingolipids is unknown. The LCB chain length is determined by serine palmitoyltransferase (SPT) isoenzymes, which are trimeric proteins composed of two large subunits (SPTLC1 and SPTLC2 or SPTLC3) and a small subunit (SPTssa or SPTssb). Here we report the identification of an Sptssb mutation, Stellar (Stl), which increased the SPT affinity toward the C18 fatty acyl-CoA substrate by twofold and significantly elevated 20-carbon (C20) LCB production in the mutant mouse brain and eye, resulting in surprising neurodegenerative effects including aberrant membrane structures, accumulation of ubiquitinated proteins on membranes, and axon degeneration. Our work demonstrates that SPT small subunits play a major role in controlling SPT activity and substrate affinity, and in specifying sphingolipid LCB chain length in vivo. Moreover, our studies also suggest that excessive C20 LCBs or C20 LCB-containing sphingolipids impair protein homeostasis and neural functions.
- Subjects :
- Molecular Sequence Data
Mutant
Serine C-Palmitoyltransferase
Biology
medicine.disease_cause
Mice
Ubiquitin
medicine
Animals
Humans
Amino Acid Sequence
SPTLC1
Peptide sequence
Mutation
Multidisciplinary
Sequence Homology, Amino Acid
Neurodegeneration
Serine C-palmitoyltransferase
Ubiquitination
Neurodegenerative Diseases
Biological Sciences
medicine.disease
Sphingolipid
Carbon
Biochemistry
biology.protein
lipids (amino acids, peptides, and proteins)
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 112
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....5e36dfb4bff58c1704775800b32d6e71