Itavastatin and Resveratrol increase triosephosphate isomerase protein (TPI) in a newly identified variant, TPIQ181P, that confers TPI deficiency

Abstract

TPI Deficiency (TPI Df) is an untreatable glycolytic enzymopathy that results in hemolytic anemia, progressive muscular impairment and irreversible brain damage. Although there is a “common” mutation (TPIE105D), other pathogenic mutations have been described. We identified patients with who are compound heterozygous for a newly-described mutation, TPIQ181P, and the common TPIE105D mutation. Intriguingly, these patients lack neuropathy or cognitive impairment. We initiated biochemical and structural studies of TPIQ181P. Surprisingly, purified TPIQ181P protein has markedly impaired catalytic properties while crystallographic studies demonstrate that TPIQ181P results in a highly disordered catalytic lid. We propose that genetic complementation is occurring between the two alleles, one with little activity (TPIQ181P) and one with low stability (TPIE105D). Consistent with this, TPIQ181P/E105D fibroblasts exhibit a significant reduction in TPI protein but much higher protein than TPIE105D/E105D fibroblasts. These data suggest that impaired stability, and not catalytic activity, is a better predictor of TPI Df severity. Lastly, we tested two recently discovered chemical modulators of mutant TPI stability and observed a significant increase in TPI in TPIQ181P/E105D patient cells.

Newly discovered roles of triosephosphate isomerase including functions within the nucleus

“…Interestingly, another TPI Df causing mutation, TPI1 Q181P , was discovered in compound heterozygous TPI Df patients alongside TPI1 E105D ( TPI1 E105D/Q181P ). The TPI1 Q181P mutation results in a protein with strongly reduced catalytic activity but increased thermal stability (VanDemark et al 2022 ). When the TPI1 Q181P allele was paired with the TPI1 E105D allele, it resulted in an atypical and less severe form of the disease, the proposed basis of which is genetic complementation between these alleles (VanDemark et al 2022 ).…”

“…The TPI1 Q181P mutation results in a protein with strongly reduced catalytic activity but increased thermal stability (VanDemark et al 2022 ). When the TPI1 Q181P allele was paired with the TPI1 E105D allele, it resulted in an atypical and less severe form of the disease, the proposed basis of which is genetic complementation between these alleles (VanDemark et al 2022 ). Understanding the basis of the genetic complementation observed in TPI Df is important to elucidate, especially considering newly discovered moonlighting functions and binding partners.…”