Evidence of a triosephosphate isomerase non-catalytic function crucial to behavior and longevity

J Cell Sci. 2013 Jul 15;126(Pt 14):3151-8. doi: 10.1242/jcs.124586. Epub 2013 May 2.

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.

Keywords: Drosophila melanogaster; Glycolysis; Locomotor function; Longevity; TPI; Triosephosphate isomerase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia, Hemolytic, Congenital Nonspherocytic / enzymology*
  • Anemia, Hemolytic, Congenital Nonspherocytic / genetics
  • Animals
  • Carbohydrate Metabolism, Inborn Errors / enzymology*
  • Carbohydrate Metabolism, Inborn Errors / genetics
  • Catalysis
  • Dihydroxyacetone Phosphate / metabolism
  • Disease Models, Animal
  • Drosophila melanogaster / enzymology
  • Drosophila melanogaster / physiology*
  • Female
  • Gene Knockout Techniques
  • Genetic Complementation Test
  • Genetic Engineering
  • Glyceraldehyde 3-Phosphate / metabolism
  • Glycolysis / genetics
  • Hot Temperature / adverse effects
  • Longevity*
  • Male
  • Mutation / genetics
  • Paralysis / enzymology*
  • Paralysis / genetics
  • Stress, Physiological / genetics
  • Transgenes / genetics
  • Triose-Phosphate Isomerase / deficiency*
  • Triose-Phosphate Isomerase / genetics
  • Triose-Phosphate Isomerase / metabolism*

Substances

  • Glyceraldehyde 3-Phosphate
  • Dihydroxyacetone Phosphate
  • Triose-Phosphate Isomerase

Supplementary concepts

  • Triosephosphate Isomerase Deficiency