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.
Subject(s)
Carbon/chemistry , Mutation , Neurodegenerative Diseases/enzymology , Serine C-Palmitoyltransferase/chemistry , Amino Acid Sequence , Animals , Humans , Mice , Molecular Sequence Data , Neurodegenerative Diseases/genetics , Sequence Homology, Amino Acid , Serine C-Palmitoyltransferase/genetics , UbiquitinationABSTRACT
ENU mutagenesis is an efficient method to identify new animal models of ocular disease. The new alleles described herein will be a useful resource to further examine the role of the affected molecules and the effects of their disruption within the retina.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 6/genetics , Disease Models, Animal , Eye Proteins/genetics , Mice, Inbred C57BL , Retinal Degeneration/genetics , Rhodopsin/genetics , Alkylating Agents/toxicity , Animals , Chromosome Mapping/methods , DNA Mutational Analysis/methods , Ethylnitrosourea/toxicity , Humans , Mice , Mutagenesis/physiology , Retinal Degeneration/chemically induced , Translational Research, Biomedical/methodsABSTRACT
In this review, we focus primarily on information obtained by studying mouse models of heritable ocular diseases. These models have proven to be important in advancing our understanding of disease etiology and of pathological consequences of heritable disorders. Careful phenotypic analyses of these models have lead to hypotheses regarding the function of various molecules as well as the mechanisms underlying the observed pathologies. Specific examples of the utility of mouse models in vision research are discussed.
