Degradation of functional TPI protein underlies sugarkill pathology
Jacquelyn L. Seigle 1, Alicia M. Celotto 1 and Michael Palladino 1*
1 University of Pittsburgh School of Medicine
* To whom correspondence should be addressed. E-mail: mjp44{at}pitt.edu.
Submitted on January 26, 2008
Revised on March 10, 2008
Accepted on 12 April 2008
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Abstract |
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TPI deficiency glycolytic enzymopathy is a progressive neurodegenerative condition that remains poorly understood. The disease is caused exclusively by specific missense mutations affecting the triose phosphate isomerase protein (TPI) 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.
Key Words:
TPI, glycolysis, neurodegeneration, proteasome, sugarkill
