Background: Triosephosphate Isomerase (TPI) is a glycolytic enzyme that is responsible for the interconversion of dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P). Depletion of TPI protein levels leads to TPI Deficiency (TPI Df): a rare, progressive neuromuscular disease which primarily affects young children. Symptoms of the disease include progressive muscle weakness, neurodegeneration, hemolytic anemia, and premature death. TPI Df is often fatal within 5 years of diagnosis, and there are extremely limited treatment options for the disease currently. TPI Df is caused exclusively by point mutations within the TPI1 gene. TPI[E105D] is the most common of these disease-causing mutations, and results in a protein which retains activity but is prematurely degraded by the cell.
Objectives: Most of the foundational work done in this disease has relied on invertebrate models, which lack in clinical relevance to human physiology. While there have been attempts to create mouse models of TPI Df in the past, none have successfully modeled the full human disease phenotype. Therefore, TPI Df pathogenesis has never been evaluated within a mammalian system. Recently, we created a novel mouse model for TPI Df by modeling the most common human disease-causing mutation.
Results: This model recapitulates the full scope of the human disease phenotype, including neuromuscular symptoms. TPI[E105D/E105D] homozygous animals and TPI[E105D/null] compound heterozygous animals both display greatly reduced lifespans, progressive muscle weakness and atrophy beginning in the hindlimbs, decreased body weight, hemolytic anemia, and postural abnormalities. As expected, TPI[E105D/null] animals have a more severe phenotype than TPI[E105D/E105D] animals. Using this model, disease pathology in the neuromuscular system was evaluated by investigating muscle health as well as neuromuscular junction integrity.
Conclusions: Study of this mammalian model may lead to a better understanding of TPI Df pathogenesis and to the development of better treatments for patients who are currently facing a devastating diagnosis.