title: Evidence of a triosephosphate isomerase non-catalytic function crucial to behavior and longevity.
abstract: Triosephosphate isomerase (TPI) is a glycolytic enzyme that converts dihydroxyacetone phosphate (DHAP) into glyceraldehyde 3-phosphate (GAP). Glycolytic enzyme dysfunction leads to metabolic diseases collectively known as glycolytic enzymopathies. Of these enzymopathies, TPI deficiency is unique in the severity of neurological symptoms. The Drosophila sugarkill mutant closely models TPI deficiency and encodes a protein prematurely degraded by the proteasome. This led us to question whether enzyme catalytic activity was crucial to the pathogenesis of TPI sugarkill neurological phenotypes. To study TPI deficiency in vivo we developed a genomic engineering system for the TPI locus that enables the efficient generation of novel TPI genetic variants. Using this system we demonstrate that TPI sugarkill can be genetically complemented by TPI encoding a catalytically inactive enzyme. Furthermore, our results demonstrate a non-metabolic function for TPI, the loss of which contributes significantly to the neurological dysfunction in this animal model.
authors: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors: Bartholomew P
authors: BP
authors: Roland
authors: Kimberly A
authors: KA
authors: Stuchul
authors: Samantha B
authors: SB
authors: Larsen
authors: Christopher G
authors: CG
authors: Amrich
authors: Andrew P
authors: AP
authors: Vandemark
authors: Alicia M
authors: AM
authors: Celotto
authors: Michael J
authors: MJ
authors: Palladino
mesh_terms: D000746:Anemia, Hemolytic, Congenital Nonspherocytic / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D002239:Carbohydrate Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics; D002384:Catalysis; D004099:Dihydroxyacetone Phosphate / Q000378:metabolism; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000201:enzymology / Q000502:physiology*; D005260:Female; D055786:Gene Knockout Techniques; D005816:Genetic Complementation Test; D005818:Genetic Engineering; D005986:Glyceraldehyde 3-Phosphate / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006358:Hot Temperature / Q000009:adverse effects; D008136:Longevity; D008297:Male; D009154:Mutation / Q000235:genetics; D010243:Paralysis / Q000201:enzymology* / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics; D019076:Transgenes / Q000235:genetics; D014305:Triose-Phosphate Isomerase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
chemical_list: D005986:Glyceraldehyde 3-Phosphate; D004099:Dihydroxyacetone Phosphate; D014305:Triose-Phosphate Isomerase
keywords: Drosophila melanogaster; Glycolysis; Locomotor function; Longevity; TPI; Triosephosphate isomerase
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