Originally published as Genetics Published Articles Ahead of Print on May 5, 2008.

Genetics, Vol. 179, 855-862, June 2008, Copyright © 2008
doi:10.1534/genetics.108.087551

Degradation of Functional Triose Phosphate Isomerase Protein Underlies sugarkill Pathology

Jacquelyn L. Seigle1, Alicia M. Celotto1 and Michael J. Palladino2

Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260

2 Corresponding author: Pittsburgh Institute for Neurodegenerative Diseases and Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, 3501 5th Ave., BST3 7042, Pittsburgh, PA 15260.
E-mail: mjp44{at}pitt.edu

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.