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Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency.

ABSTRACT: Triosephosphate isomerase (TPI) deficiency is a fatal genetic disorder characterized by hemolytic anemia and neurological dysfunction. Although the enzyme defect in TPI was discovered in the 1960s, the exact etiology of the disease is still debated. Some aspects indicate the disease could be caused by insufficient enzyme activity, whereas other observations indicate it could be a protein misfolding disease with tissue-specific differences in TPI activity. We generated a mouse model in which exchange of a conserved catalytic amino acid residue (isoleucine to valine, Ile170Val) reduces TPI specific activity without affecting the stability of the protein dimer. TPIIle170Val/Ile170Val mice exhibit an approximately 85% reduction in TPI activity consistently across all examined tissues, which is a stronger average, but more consistent, activity decline than observed in patients or symptomatic mouse models that carry structural defect mutant alleles. While monitoring protein expression levels revealed no evidence for protein instability, metabolite quantification indicated that glycolysis is affected by the active site mutation. TPIIle170Val/Ile170Val mice develop normally and show none of the disease symptoms associated with TPI deficiency. Therefore, without the stability defect that affects TPI activity in a tissue-specific manner, a strong decline in TPI catalytic activity is not sufficient to explain the pathological onset of TPI deficiency.

SUBMITTER: Segal J

PROVIDER: S-EPMC7887927 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency.

Segal Joanna J Mülleder Michael M Krüger Antje A Adler Thure T Scholze-Wittler Manuela M Becker Lore L Calzada-Wack Julia J Garrett Lillian L Hölter Sabine M SM Rathkolb Birgit B Rozman Jan J Racz Ildiko I Fischer Ralf R Busch Dirk H DH Neff Frauke F Klingenspor Martin M Klopstock Thomas T Grüning Nana-Maria NM Michel Steve S Lukaszewska-McGreal Beata B Voigt Ingo I Hartmann Ludger L Timmermann Bernd B Lehrach Hans H Wolf Eckhard E Wurst Wolfgang W Gailus-Durner Valérie V Fuchs Helmut H H de Angelis Martin M Schrewe Heinrich H Yuneva Mariia M Ralser Markus M

Journal of inherited metabolic disease 20190611 5

Triosephosphate isomerase (TPI) deficiency is a fatal genetic disorder characterized by hemolytic anemia and neurological dysfunction. Although the enzyme defect in TPI was discovered in the 1960s, the exact etiology of the disease is still debated. Some aspects indicate the disease could be caused by insufficient enzyme activity, whereas other observations indicate it could be a protein misfolding disease with tissue-specific differences in TPI activity. We generated a mouse model in which exch ...[more]

PMID: 31111503

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Project description:Triosephosphate isomerase (TPI) deficiency is a unique glycolytic enzymopathy coupled with neurodegeneration. Two Hungarian compound heterozygote brothers inherited the same TPI mutations (F240L and E145Stop), but only the younger one suffers from neurodegeneration. In the present study, we determined the kinetic parameters of key glycolytic enzymes including the mutant TPI for rational modelling of erythrocyte glycolysis. We found that a low TPI activity in the mutant cells (lower than predicted from the protein level and specific activity of the purified recombinant enzyme) is coupled with an increase in the activities of glycolytic kinases. The modelling rendered it possible to establish the steady-state flux of the glycolysis and metabolite concentrations, which was not possible experimentally due to the inactivation of the mutant TPI and other enzymes during the pre-steady state. Our results showed that the flux was 2.5-fold higher and the concentration of DHAP (dihydroxyacetone phosphate) and fructose 1,6-bisphosphate increased 40- and 5-fold respectively in the erythrocytes of the patient compared with the control. Although the rapid equilibration of triosephosphates is not achieved, the energy state of the cells is not 'sick' due to the activation of key regulatory enzymes. In lymphocytes of the two brothers, the TPI activity was also lower (20%) than that of controls; however, the remaining activity was high enough to maintain the rapid equilibration of triosephosphates; consequently, no accumulation of DHAP occurs, as judged by our experimental and computational data. Interestingly, we found significant differences in the mRNA levels of the brothers for TPI and some other, apparently unrelated, proteins. One of them is the prolyl oligopeptidase, the activity decrease of which has been reported in well-characterized neurodegenerative diseases. We found that the peptidase activity of the affected brother was reduced by 30% compared with that of his neurologically intact brother.

Dataset Information

Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency.

Publications

Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency.

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