GAPDH binders as potential drugs for the therapy of polyglutamine diseases: Design of a new screening assay

Lazarev, Vladimir F.; Benken, Konstantin A.; Semenyuk, Pavel I.; Саранцева, С. В.; Bolshakova, O. I.; Mikhaylova, Elena R.; Muronetz, Vladimir I.; Guzhova, Irina V.; Margulis, Boris A.

doi:10.1016/j.febslet.2015.01.018

Cited by 22 publications

(18 citation statements)

References 32 publications

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“…We propose that novel anti-HD therapies might be developed by first understanding the significance of the roles played by the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in polyQ aggregation and transport. Work in our lab has shown that GAPDH forms a strong complex with mutant huntingtin and increases its cytotoxicity in cell and animal models of polyQ pathologies [3,4]. We have also shown the GAPDH is found in aggregates formed by proteins released from dying PC-12 cells overexpressing the Q103 repeat.…”

Section: Introductionmentioning

confidence: 65%

A hydrocortisone derivative binds to GAPDH and reduces the toxicity of extracellular polyglutamine-containing aggregates

Lazarev

Mikhaylova

Dutysheva

et al. 2017

Biochemical and Biophysical Research Communications

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Section: Introductionmentioning

confidence: 65%

A hydrocortisone derivative binds to GAPDH and reduces the toxicity of extracellular polyglutamine-containing aggregates

Lazarev

Mikhaylova

Dutysheva

et al. 2017

Biochemical and Biophysical Research Communications

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“…GAPDH was previously shown to form cytotoxic aggregating complexes with long polyQ repeats in HD in vitro and in Ataxia 3 in vivo models (Lazarev et al . ). We hypothesized that these aggregates were able to migrate from pathogenic cells to other regions of the brain in a prion‐like manner (Ren et al .…”

Section: Resultsmentioning

confidence: 97%

“…Thus, the enzyme significantly increases the lethal effect of polyQ not only in cells over‐producing mHTT (Lazarev et al . ), but also in the culture medium.…”

Section: Resultsmentioning

confidence: 99%

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Glyceraldehyde 3‐phosphate dehydrogenase augments the intercellular transmission and toxicity of polyglutamine aggregates in a cell model of Huntington disease

Mikhaylova

Lazarev

Nikotina

et al. 2016

Journal of Neurochemistry

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The common feature of Huntington disease is the accumulation of oligomers or aggregates of mutant huntingtin protein (mHTT), which causes the death of a subset of striatal neuronal populations. The cytotoxic species can leave neurons and migrate to other groups of cells penetrating and damaging them in a prion-like manner. We hypothesized that the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH), previously shown to elevate the aggregation of mHTT, is associated with an increased efficiency of intercellular propagation of mHTT. GAPDH, on its own or together with polyglutamine species, was shown to be released into the extracellular milieu mainly from dying cells as assessed by a novel enzyme immunoassay, western blotting, and ultrafiltration. The conditioned medium of cells with growing GAPDH-polyQ aggregates was toxic to na€ ıve cells, whereas depletion of the aggregates from the medium lowered this cytotoxicity. The GAPDH component of the aggregates was found to increase their toxicity by two-fold in comparison with polyQ alone. Furthermore, GAPDH-polyQ complexes were shown to penetrate acceptor cells and to increase the capacity of polyQ to prionize its intracellular homolog containing a repeat of 25 glutamine residues. Finally, inhibitors of intracellular transport showed that polyQ-GAPDH complexes, as well as GAPDH itself, penetrated cells using clathrin-mediated endocytosis. This suggested a pivotal role of the enzyme in the intercellular transmission of Huntington disease pathogenicity. In conclusion, GAPDH occurring in complexes with polyglutamine strengthens the prion-like activity and toxicity of the migrating aggregates.

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“…Based on these findings, we suggested previously a critical role for GAPDH aggregation in oxidative stress-induced neuronal cell death both in vitro and in vivo (14, 15, 24, 25). Further, GAPDH aggregation is likely related to the pathogeneses of amyotrophic lateral sclerosis and Huntington's disease (26, 27). However, the detailed mechanisms for cell death induced by GAPDH aggregation in the context of these pathogeneses remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Aggregation Causes Mitochondrial Dysfunction during Oxidative Stress-induced Cell Death

Nakajima

Itakura

Kubo

et al. 2017

Journal of Biological Chemistry

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Glycolytic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional protein that also mediates cell death under oxidative stress. We reported previously that the active-site cysteine (Cys-152) of GAPDH plays an essential role in oxidative stress-induced aggregation of GAPDH associated with cell death, and a C152A-GAPDH mutant rescues nitric oxide (NO)-induced cell death by interfering with the aggregation of wild type (WT)-GAPDH. However, the detailed mechanism underlying GAPDH aggregate-induced cell death remains elusive. Here we report that NO-induced GAPDH aggregation specifically causes mitochondrial dysfunction. First, we observed a correlation between NO-induced GAPDH aggregation and mitochondrial dysfunction, when GAPDH aggregation occurred at mitochondria in SH-SY5Y cells. In isolated mitochondria, aggregates of WT-GAPDH directly induced mitochondrial swelling and depolarization, whereas mixtures containing aggregates of C152A-GAPDH reduced mitochondrial dysfunction. Additionally, treatment with cyclosporin A improved WT-GAPDH aggregate-induced swelling and depolarization. In doxycycline-inducible SH-SY5Y cells, overexpression of WT-GAPDH augmented NO-induced mitochondrial dysfunction and increased mitochondrial GAPDH aggregation, whereas induced overexpression of C152A-GAPDH significantly suppressed mitochondrial impairment. Further, NO-induced cytochrome c release into the cytosol and nuclear translocation of apoptosis-inducing factor from mitochondria were both augmented in cells overexpressing WT-GAPDH but ameliorated in C152A-GAPDH-overexpressing cells. Interestingly, GAPDH aggregates induced necrotic cell death via a permeability transition pore (PTP) opening. The expression of either WT- or C152A-GAPDH did not affect other cell death pathways associated with protein aggregation, such as proteasome inhibition, gene expression induced by endoplasmic reticulum stress, or autophagy. Collectively, these results suggest that NO-induced GAPDH aggregation specifically induces mitochondrial dysfunction via PTP opening, leading to cell death.

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GAPDH binders as potential drugs for the therapy of polyglutamine diseases: Design of a new screening assay

Cited by 22 publications

References 32 publications

A hydrocortisone derivative binds to GAPDH and reduces the toxicity of extracellular polyglutamine-containing aggregates

A hydrocortisone derivative binds to GAPDH and reduces the toxicity of extracellular polyglutamine-containing aggregates

Glyceraldehyde 3‐phosphate dehydrogenase augments the intercellular transmission and toxicity of polyglutamine aggregates in a cell model of Huntington disease

Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Aggregation Causes Mitochondrial Dysfunction during Oxidative Stress-induced Cell Death

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