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Oxidatively modified glyceraldehyde-3-phosphate dehydrogenase in neurodegenerative processes and the role of low molecular weight compounds in counteracting its aggregation and nuclear translocation.
Ageing Res Rev. 2018 Dec; 48:21-31.AR

Abstract

A number of independent studies have shown the contribution of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the pathogenesis of several neurodegenerative disorders. Indeed, GAPDH aggregates have been found in many post-mortem samples of brains of patients diagnosed with Alzheimer's and Parkinson disease. Currently, it is accepted that GAPDH-mediated cell death pathways in the neurodegenerative processes are associated with apoptosis caused by GAPDH nuclear translocation and excessive aggregation under oxidative stress conditions. Also the role of GAPDH in neurodegenerative diseases is linked to it directly binding to specific amyloidogenic proteins and petides such as β-amyloid precursor protein, β-amyloid peptide and tau protein in Alzheimer's disease, huntingtin in Huntington's disease and α-synuclein in Parkinson disease. One of the latest studies indicated that GAPDH aggregates significantly accelerate amyloidogenesis of the β-amyloid peptide, which implies that aggregates of GAPDH may act as a specific aggregation "seed" in vitro. Previous detailed studies revealed that the active-site cysteine (Cys152) of GAPDH plays an essential role in the oxidative stress-induced aggregation of GAPDH associated with cell death. Furthermore, oxidative modification of this cysteine residue initiates the translocation of the enzyme to the nucleus, subsequently leading to apoptosis. The crystallographic structure of GAPDH shows that the Cys152 residue is located close to the surface of the molecule in a hydrophilic environment, which means that it can react with low molecular weight compounds such as hydroxynonenal or piceatannol. Therefore, it is highly possible that GAPDH may serve as a target for small molecule compounds with the potential to slow down or prevent the progression of neurodegenerative disorders. Recently appearing new evidence has highlighted the significance of low molecular weight compounds in counteracting the oxidation of GAPDH and consequently its aggregation and other unfavourable pathological processes. Hence, this review aims to present all recent findings concerning molecules that are able to interact with GAPDH and counteract its aggregation and translocation to the nucleus.

Authors+Show Affiliations

Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland; Bionanopark Ltd., Lodz, Poland. Electronic address: joanna.gerszon@biol.uni.lodz.pl.Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

30254002

Citation

Gerszon, Joanna, and Aleksandra Rodacka. "Oxidatively Modified Glyceraldehyde-3-phosphate Dehydrogenase in Neurodegenerative Processes and the Role of Low Molecular Weight Compounds in Counteracting Its Aggregation and Nuclear Translocation." Ageing Research Reviews, vol. 48, 2018, pp. 21-31.
Gerszon J, Rodacka A. Oxidatively modified glyceraldehyde-3-phosphate dehydrogenase in neurodegenerative processes and the role of low molecular weight compounds in counteracting its aggregation and nuclear translocation. Ageing Res Rev. 2018;48:21-31.
Gerszon, J., & Rodacka, A. (2018). Oxidatively modified glyceraldehyde-3-phosphate dehydrogenase in neurodegenerative processes and the role of low molecular weight compounds in counteracting its aggregation and nuclear translocation. Ageing Research Reviews, 48, 21-31. https://doi.org/10.1016/j.arr.2018.09.003
Gerszon J, Rodacka A. Oxidatively Modified Glyceraldehyde-3-phosphate Dehydrogenase in Neurodegenerative Processes and the Role of Low Molecular Weight Compounds in Counteracting Its Aggregation and Nuclear Translocation. Ageing Res Rev. 2018;48:21-31. PubMed PMID: 30254002.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oxidatively modified glyceraldehyde-3-phosphate dehydrogenase in neurodegenerative processes and the role of low molecular weight compounds in counteracting its aggregation and nuclear translocation. AU - Gerszon,Joanna, AU - Rodacka,Aleksandra, Y1 - 2018/09/22/ PY - 2018/07/31/received PY - 2018/09/04/revised PY - 2018/09/13/accepted PY - 2018/9/27/pubmed PY - 2019/7/30/medline PY - 2018/9/27/entrez KW - Cysteine oxidation KW - Glyceraldehyde-3-phosphate dehydrogenase KW - Low molecular weight compounds KW - Neurodegenerative diseases KW - Protein aggregation SP - 21 EP - 31 JF - Ageing research reviews JO - Ageing Res. Rev. VL - 48 N2 - A number of independent studies have shown the contribution of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the pathogenesis of several neurodegenerative disorders. Indeed, GAPDH aggregates have been found in many post-mortem samples of brains of patients diagnosed with Alzheimer's and Parkinson disease. Currently, it is accepted that GAPDH-mediated cell death pathways in the neurodegenerative processes are associated with apoptosis caused by GAPDH nuclear translocation and excessive aggregation under oxidative stress conditions. Also the role of GAPDH in neurodegenerative diseases is linked to it directly binding to specific amyloidogenic proteins and petides such as β-amyloid precursor protein, β-amyloid peptide and tau protein in Alzheimer's disease, huntingtin in Huntington's disease and α-synuclein in Parkinson disease. One of the latest studies indicated that GAPDH aggregates significantly accelerate amyloidogenesis of the β-amyloid peptide, which implies that aggregates of GAPDH may act as a specific aggregation "seed" in vitro. Previous detailed studies revealed that the active-site cysteine (Cys152) of GAPDH plays an essential role in the oxidative stress-induced aggregation of GAPDH associated with cell death. Furthermore, oxidative modification of this cysteine residue initiates the translocation of the enzyme to the nucleus, subsequently leading to apoptosis. The crystallographic structure of GAPDH shows that the Cys152 residue is located close to the surface of the molecule in a hydrophilic environment, which means that it can react with low molecular weight compounds such as hydroxynonenal or piceatannol. Therefore, it is highly possible that GAPDH may serve as a target for small molecule compounds with the potential to slow down or prevent the progression of neurodegenerative disorders. Recently appearing new evidence has highlighted the significance of low molecular weight compounds in counteracting the oxidation of GAPDH and consequently its aggregation and other unfavourable pathological processes. Hence, this review aims to present all recent findings concerning molecules that are able to interact with GAPDH and counteract its aggregation and translocation to the nucleus. SN - 1872-9649 UR - https://www.unboundmedicine.com/medline/citation/30254002/Oxidatively_modified_glyceraldehyde_3_phosphate_dehydrogenase_in_neurodegenerative_processes_and_the_role_of_low_molecular_weight_compounds_in_counteracting_its_aggregation_and_nuclear_translocation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1568-1637(18)30176-4 DB - PRIME DP - Unbound Medicine ER -