Degradation of Functional Triose Phosphate Isomerase Protein Underlies<i>sugarkill</i>Pathology

Seigle, Jacquelyn L; Celotto, Alicia M.; Palladino, Michael J.

doi:10.1534/genetics.108.087551

Cited by 30 publications

(56 citation statements)

References 51 publications

(81 reference statements)

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“…Genetic data suggested that TPI sgk retained sufficient function to rescue mutant survival and behavioral phenotypes if overexpressed (Seigle et al, 2008). These data led us to hypothesize that reduced TPI catalysis was crucial to the pathogenesis of TPI deficiency.…”

Section: Recombinant Tpi Enzyme Activitymentioning

confidence: 98%

“…Previous studies established that TPI sgk is a recessive loss-offunction mutation characterized by reduced TPI levels (Seigle et al, 2008). Genetic data suggested that TPI sgk retained sufficient function to rescue mutant survival and behavioral phenotypes if overexpressed (Seigle et al, 2008).…”

Section: Recombinant Tpi Enzyme Activitymentioning

confidence: 99%

“…2A). Previously, we have shown that TPI sgk phenotypes are progressive in nature (Celotto et al, 2006;Seigle et al, 2008). We measured these behaviors at two time points, day 3 and day 20, to reveal whether TPI K11M fully complements the TPI sgk phenotypes or simply delays their onset.…”

Section: Recombinant Tpi Enzyme Activitymentioning

confidence: 99%

“…The affected methionine is present near the dimer interface yet does not seem to result in a shift in monomer-dimer populations in vivo (Seigle et al, 2008). However, the TPI sgk mutation has been shown to induce abnormal proteasomal degradation of TPI resulting in reduced total TPI protein (Seigle et al, 2008;Hrizo and Palladino, 2010). Interestingly, we have previously shown that this loss-of-function mutation can be attenuated by overexpressing mutant TPI sgk (Celotto et al, 2006).…”

Section: Introductionmentioning

confidence: 95%

“…TPI sgk is characterized by shortened lifespan, neurodegeneration, and conditional behavioral abnormalities (Celotto et al, 2006) resulting from a missense mutation causing a methionine to threonine substitution (M80T). The affected methionine is present near the dimer interface yet does not seem to result in a shift in monomer-dimer populations in vivo (Seigle et al, 2008). However, the TPI sgk mutation has been shown to induce abnormal proteasomal degradation of TPI resulting in reduced total TPI protein (Seigle et al, 2008;Hrizo and Palladino, 2010).…”

Section: Introductionmentioning

confidence: 99%

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

Roland

Stuchul

Larsen

et al. 2013

Journal of Cell Science

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SummaryTriosephosphate 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.

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Section: Recombinant Tpi Enzyme Activitymentioning

confidence: 98%

Section: Recombinant Tpi Enzyme Activitymentioning

confidence: 99%

Section: Recombinant Tpi Enzyme Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Roland

Stuchul

Larsen

et al. 2013

Journal of Cell Science

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A novel DrosophilaSOD2 mutant demonstrates a role for mitochondrial ROS in neurodevelopment and disease

et al. 2012

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Reactive oxygen species (ROS) play essential roles in cell signaling, survival, and homeostasis. Aberrant ROS lead to disease and contribute to the aging process. Numerous enzymes and vigilant antioxidant pathways are required to regulate ROS for normal cellular health. Mitochondria are a major source of ROS, and mechanisms to prevent elevated ROS during oxidative phosphorylation require super oxide dismutase (SOD) activity. SOD2, also known as MnSOD, is targeted to mitochondria and is instrumental in regulating ROS by conversion of superoxides to hydrogen peroxide, which is further broken down into H2O and oxygen. Here, we describe the identification of a novel mutation within the mitochondrial SOD2 enzyme in Drosophila that results in adults with an extremely shortened life span, sensitivity to hyperoxia, and neuropathology. Additional studies demonstrate that this novel mutant, SOD2bewildered, exhibits abnormal brain morphology, suggesting a critical role for this protein in neurodevelopment. We investigated the basis of this neurodevelopmental defect and discovered an increase in aberrant axonal that could underlie the aberrant neurodevelopment and brain morphology defects. This novel allele, SOD2bewildered, provides a unique opportunity to study the effects of increased mitochondrial ROS on neural development, axonal targeting, and neural cell degeneration in vivo.

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A guide to the effects of a large portion of the residues of triosephosphate isomerase on catalysis, stability, druggability, and human disease

et al. 2017

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Triosephosphate isomerase (TIM) is a ubiquitous enzyme, which appeared early in evolution. TIM is responsible for obtaining net ATP from glycolysis and producing an extra pyruvate molecule for each glucose molecule, under aerobic and anaerobic conditions. It is placed in a metabolic crossroad that allows a quick balance of the triose phosphate aldolase produced by glycolysis, and is also linked to lipid metabolism through the alternation of glycerol-3-phosphate and the pentose cycle. TIM is one of the most studied enzymes with more than 199 structures deposited in the PDB. The interest for this enzyme stems from the fact that it is involved in glycolysis, but also in aging, human diseases and metabolism. TIM has been a target in the search for chemical compounds against infectious diseases and is a model to study catalytic features. Until February 2017, 62% of all residues of the protein have been studied by mutagenesis and/or using other approaches. Here, we present a detailed and comprehensive recompilation of the reported effects on TIM catalysis, stability, druggability and human disease produced by each of the amino acids studied, contributing to a better understanding of the properties of this fundamental protein. The information reviewed here shows that the role of the noncatalytic residues depend on their molecular context, the delicate balance between the short and long-range interactions in concerted action determining the properties of the protein. Each protein should be regarded as a unique entity that has evolved to be functional in the organism to which it belongs. Proteins 2017; 85:1190-1211. © 2017 Wiley Periodicals, Inc.

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Degradation of Functional Triose Phosphate Isomerase Protein UnderliessugarkillPathology

Cited by 30 publications

References 51 publications

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

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

A novel DrosophilaSOD2 mutant demonstrates a role for mitochondrial ROS in neurodevelopment and disease

A guide to the effects of a large portion of the residues of triosephosphate isomerase on catalysis, stability, druggability, and human disease

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