title: Degradation of functional triose phosphate isomerase protein underlies sugarkill pathology.
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 TPI(sugarkill) 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.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Jacquelyn L
authors.initials: JL
authors.lastname: Seigle
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Celotto
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Palladino
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019281:Dimerization; D004330:Drosophila / Q000201:enzymology* / Q000235:genetics*; D004795:Enzyme Stability; D015870:Gene Expression; D017344:Genes, Insect; D005808:Genes, Recessive; D006801:Humans; D008136:Longevity / Q000235:genetics / Q000502:physiology; D008957:Models, Genetic; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020836:Protein Structure, Quaternary; D014305:Triose-Phosphate Isomerase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*
chemical_list: D046988:Proteasome Endopeptidase Complex; D014305:Triose-Phosphate Isomerase