1. Degradation of Functional Triose Phosphate Isomerase Protein Underlies sugarkill Pathology
- Author
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Alicia M. Celotto, Jacquelyn L Seigle, and Michael J. Palladino
- Subjects
Proteasome Endopeptidase Complex ,Longevity ,Mutation, Missense ,Gene Expression ,Genes, Insect ,Genes, Recessive ,Motor Activity ,Investigations ,Biology ,medicine.disease_cause ,Triosephosphate isomerase ,Animals, Genetically Modified ,Pathogenesis ,chemistry.chemical_compound ,Mutant protein ,DHAP ,Enzyme Stability ,parasitic diseases ,Genetics ,medicine ,Animals ,Humans ,Missense mutation ,Glycolysis ,Protein Structure, Quaternary ,Dihydroxyacetone phosphate ,Mutation ,Models, Genetic ,chemistry ,Biochemistry ,Drosophila ,Dimerization ,Triose-Phosphate Isomerase - Abstract
Triose phosphate isomerase (TPI) deficiency glycolytic enzymopathy is a progressive neurodegenerative condition that remains poorly understood. The disease is caused exclusively by specific missense mutations affecting the TPI protein and clinically features hemolytic anemia, adult-onset neurological impairment, degeneration, and reduced longevity. TPI has a well-characterized role in glycolysis, catalyzing the isomerization of dihydroxyacetone phosphate (DHAP) to glyceraldehyde-3-phosphate (G3P); however, little is known mechanistically about the pathogenesis associated with specific recessive mutations that cause progressive neurodegeneration. Here, we describe key aspects of TPI pathogenesis identified using the TPIsugarkill mutation, a Drosophila model of human TPI deficiency. Specifically, we demonstrate that the mutant protein is expressed, capable of forming a homodimer, and is functional. However, the mutant protein is degraded by the 20S proteasome core leading to loss-of-function pathogenesis.
- Published
- 2008