Glyceraldehyde-3-phosphate dehydrogenase as a target for small-molecule disease-modifying therapies in human neurodegenerative disorders

Glyceraldehyde-3-phosphate dehydrogenase as a target for small-molecule disease-modifying therapies in human neurodegenerative disorders

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J Psychiatry Neurosci 2004;29(5):337-345

Mark D. Berry

ALviva Biopharmaceuticals Inc., Saskatoon, Sask.

Abstract

Recent articles have highlighted numerous additional functions of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) that are independent of its well-documented glycolytic function. One of the most intriguing of these functions is as an initiator of programmed cell death cascades. This activity involves a nuclear appearance of GAPDH, a considerable proportion of which requires synthesis of new GAPDH protein and has characteristics suggesting the involvement of a novel isozyme. The relevance of such findings to human neurodegenerative conditions is emphasized by the increased nuclear GAPDH observed in postmortem samples from patients with Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and glaucoma, among others. A number of small-molecule compounds have now been identified that show anti-apoptotic activity because of their ability to interact with GAPDH and prevent its nuclear accumulation. These compounds, one of which is currently being tested in late-stage Phase II clinical trials as a disease-modifying therapy for Parkinson’s disease, have potential utility in the treatment of human neurodegenerative conditions.

Résumé

Des articles récents ont décrit de nombreuses fonctions supplémentaires de la glycéraldéhyde-3-phosphate déshydrogénase (GAPDH) indépendantes de sa fonction glycolytique bien documentée. Une des plus intrigantes de ces fonctions est celle de catalyseur de cascades d’apoptose. Cette activité met en cause une apparition dans le noyau de la GAPDH, dont une proportion importante nécessite la synthèse de nouvelle protéine de GAPDH et a des caractéristiques qui indiquent la présence d’un isozyme nouveau. L’élévation de la GAPDH nucléaire observée dans des échantillons postmortem prélevés chez des patients atteints de la maladie de Parkinson, la maladie d’Alzheimer, la chorée d’Huntington et le glaucome, notamment, met en évidence la pertinence de ces constatations dans le cas de problèmes neurodégénératifs humains. On a maintenant identifié un certain nombre de composés à petites molécules qui ont une activité antiapoptotique parce qu’ils peuvent réagir avec la GAPDH et l’empêcher de s’accumuler dans le noyau. Ces composés, dont l’un fait actuellement l’objet d’essais cliniques de phase II, qui achèvent, comme traitement de fond contre la maladie de Parkinson, offrent des possibilités pour le traitement des maladies neurodégénératives humaines.


Medical subject headings: apoptosis; drug therapy; glyceraldehyde-3-phosphate dehydrogenase; neurodegenerative diseases.

Submitted June 3, 2003; Revised Oct. 15, 2003; Accepted Oct. 20, 2003

Acknowledgements: The author gratefully acknowledges Dr. Paula Ashe for helpful discussions and for making preliminary data available for publication, and he acknowledges Drs. Alan A. Boulton and Bruce A. Davis for their critical appraisal of the manuscript.

Competing interests: Dr. Berry was employed by ALviva Biopharmaceuticals at the time of writing and owns stock options in the company.

Correspondence to: Dr. Mark D. Berry, Department of Chemistry, J.R. Brodie Science Centre, Brandon University, Brandon MB R7A 6A9; fax 204 728-7346; berrym@brandonu.ca