Missense variant in TPI1 (Arg189Gln) causes neurologic deficits through structural changes in the triosephosphate isomerase catalytic site and reduced enzyme levels in vivo

Roland, Bartholomew P.; Richards, Kristen R.; Hrizo, Stacy; Eicher, Samantha L; Barile, Zackery; Chang, Tien‐Chien; Savon, Grace; Bianchi, Paola; Fermo, Elisa; Ricerca, Bianca Maria; Tortorolo, Luca; Vockley, Jerry; VanDemark, Andrew P.; Palladino, Michael J.

doi:10.1016/j.bbadis.2019.05.002

Cited by 19 publications

(15 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are limited patient data from asymptomatic controls, but a published case included a heterozygote mother with a reduced TPI of 584 UI/g hemoglobin (Hb; ~25–30% of the adult reference range of 1407–2133) who was completely asymptomatic. 5 In contrast, her child had TPI levels of 289 UI/g Hb (~14–20% of the adult reference range) with severe early-onset TPI Df. 5 These data suggest that fully rescuing TPI to wild-type levels is not necessary to have an extremely significant therapeutic benefit and that modest increases would be of therapeutic value even if they did not fully prevent all disease symptoms.…”

Section: Discussionmentioning

confidence: 95%

“…5 In contrast, her child had TPI levels of 289 UI/g Hb (~14–20% of the adult reference range) with severe early-onset TPI Df. 5 These data suggest that fully rescuing TPI to wild-type levels is not necessary to have an extremely significant therapeutic benefit and that modest increases would be of therapeutic value even if they did not fully prevent all disease symptoms. Future studies will be needed to verify whether these compounds work similarly in compound-heterozygous TPI Df patient cells and to test efficacy in vivo.…”

Section: Discussionmentioning

confidence: 95%

“…Positives that emerge from this effort can be tested in a variety of patient fibroblasts that represent the whole spectrum of disease and in a well-validated in vivo Drosophila model. 5,7 These secondary assays will include measurements of mutant TPI half-life by pulse-chase experiments and activity using an enzymatic assay. 17 Final validation will occur in a mouse model of TPI-Df that is currently being developed and, while not having been fully validated yet, shows hallmarks of the human disease (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…The most common TPI Df mutation is the TPI E105D (aka E104D in legacy publications); patients with this mutation can be homozygous TPI E105D/E105D or compound heterozygous, typically with TPI E105D and another pathogenic missense mutation resulting in disease. 5 These genetic mutations primarily affect the stability of mutant TPI protein. 6 While the mutant protein dimer remains catalytically active and functional, it has been shown for several pathogenic mutations that the mutant protein is targeted for degradation through the protein quality control (PQC) pathway, leading to very low levels of TPI within the cell.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A High-Content Screening Assay for Small Molecules That Stabilize Mutant Triose Phosphate Isomerase (TPI) as Treatments for TPI Deficiency

et al. 2021

Self Cite

View full text Add to dashboard Cite

Triose phosphate isomerase deficiency (TPI Df) is an untreatable, childhood-onset glycolytic enzymopathy. Patients typically present with frequent infections, anemia, and muscle weakness that quickly progresses with severe neuromusclar dysfunction requiring aided mobility and often respiratory support. Life expectancy after diagnosis is typically ~5 years. There are several described pathogenic mutations that encode functional proteins; however, these proteins, which include the protein resulting from the “common” TPIE105D mutation, are unstable due to active degradation by protein quality control (PQC) pathways. Previous work has shown that elevating mutant TPI levels by genetic or pharmacological intervention can ameliorate symptoms of TPI Df in fruit flies. To identify compounds that increase levels of mutant TPI, we have developed a human embryonic kidney (HEK) stable knock-in model expressing the common TPI Df protein fused with green fluorescent protein (HEK TPIE105D-GFP). To directly address the need for lead TPI Df therapeutics, these cells were developed into an optical drug discovery platform that was implemented for high-throughput screening (HTS) and validated in 3-day variability tests, meeting HTS standards. We initially used this assay to screen the 446-member National Institutes of Health (NIH) Clinical Collection and validated two of the hits in dose–response, by limited structure–activity relationship studies with a small number of analogs, and in an orthogonal, non-optical assay in patient fibroblasts. The data form the basis for a large-scale phenotypic screening effort to discover compounds that stabilize TPI as treatments for this devastating childhood disease.

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A High-Content Screening Assay for Small Molecules That Stabilize Mutant Triose Phosphate Isomerase (TPI) as Treatments for TPI Deficiency

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Polymorphisms in ADH1B associated with the increased risk of gastric cancer (Ghosh et al, 2017 (Chen et al, 2015), and promotion of pancreatic cancer progression (Cui et al, 2015). (Roland et al, 2019).…”

Section: Molecular Dockingmentioning

confidence: 99%

Inverse molecular docking reveals a novel function of thymol: Inhibition of fat deposition induced by high‐dose glucose in Caenorhabditis elegans

Ban

Zhou

et al. 2021

Food Science & Nutrition

View full text Add to dashboard Cite

show abstract

LncRNA‐Mediated TPI1 and PKM2 Promote Self‐Renewal and Chemoresistance in GBM

Yang,

Li,

Tian

et al. 2024

Advanced Science

View full text Add to dashboard Cite

Temozolomide (TMZ) resistance is one of the major reasons for poor prognosis in patients with glioblastoma (GBM). Long noncoding RNAs (lncRNAs) are involved in multiple biological processes, including TMZ resistance. Linc00942 is a potential regulator of TMZ sensitivity in GBM cells is shown previously. However, the underlying mechanism of TMZ resistance induced by Linc00942 is unknown. In this study, the sequence of Linc00942 by rapid amplification of cDNA ends assay in TMZ‐resistant GBM cells is identified and confirmed that Linc00942 contributes to self‐renewal and TMZ resistance in GBM cells. Chromatin isolation by RNA purification followed by mass spectrometry (ChIRP‐MS) and followed by Western blotting (ChIRP‐WB) assays shows that Linc00492 interacted with TPI1 and PKM2, subsequently promoting their phosphorylation, dimerization, and nuclear translocation. The interaction of Linc00942 with TPI1 and PKM2 leads to increased acetylation of H3K4 and activation of the STAT3/P300 axis, resulting in the marked transcriptional activation of SOX9. Moreover, the knockdown of SOX9 reversed TMZ resistance induced by Linc00492 both in vitro and in vivo. In summary, Linc00942 strongly promotes SOX9 expression by interacting with TPI1 and PKM2 is found, thereby driving self‐renewal and TMZ resistance in GBM cells. These findings suggest potential combined therapeutic strategies to overcome TMZ resistance in patients with GBM.

show abstract

Missense variant in TPI1 (Arg189Gln) causes neurologic deficits through structural changes in the triosephosphate isomerase catalytic site and reduced enzyme levels in vivo

Cited by 19 publications

References 55 publications

A High-Content Screening Assay for Small Molecules That Stabilize Mutant Triose Phosphate Isomerase (TPI) as Treatments for TPI Deficiency

A High-Content Screening Assay for Small Molecules That Stabilize Mutant Triose Phosphate Isomerase (TPI) as Treatments for TPI Deficiency

Inverse molecular docking reveals a novel function of thymol: Inhibition of fat deposition induced by high‐dose glucose in Caenorhabditis elegans

LncRNA‐Mediated TPI1 and PKM2 Promote Self‐Renewal and Chemoresistance in GBM

Contact Info

Product

Resources

About