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Canadian Association of Neurosciences Review: Polyglutamine Expansion Neurodegenerative Diseases

Published online by Cambridge University Press:  02 December 2014

Ray Truant ,
Lynn A. Raymond ,
Jianrun Xia ,
Deborah Pinchev ,
Anjee Burtnik  and
Randy Singh Atwal
Ray Truant*
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
Lynn A. Raymond
Affiliation:
Division of Neuroscience, Department of Psychiatry and Brain Research Centre, Vancouver, BC, Canada
Jianrun Xia
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
Deborah Pinchev
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
Anjee Burtnik
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
Randy Singh Atwal
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
*
Department of Biochemistry and Biomedical Sciences, McMaster University, HSC 4H45 1200 Main Street West, Hamilton, Ontario, L8N 3Z5, Canada.
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Abstract:

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Since the early 1990s, DNA triplet repeat expansions have been found to be the cause in an ever increasing number of genetic neurologic diseases. A subset of this large family of genetic diseases has the expansion of a CAG DNA triplet in the open reading frame of a coding exon. The result of this DNA expansion is the expression of expanded glutamine amino acid repeat tracts in the affected proteins, leading to the term, Polyglutamine Diseases, which is applied to this sub-family of diseases. To date, nine distinct genes are known to be linked to polyglutamine diseases, including Huntington's disease, Machado-Joseph Disease and spinobulbar muscular atrophy or Kennedy's disease. Most of the polyglutamine diseases are characterized clinically as spinocerebellar ataxias. Here we discuss recent successes and advancements in polyglutamine disease research, comparing these different diseases with a common genetic flaw at the level of molecular biology and early drug design for a family of diseases where many new research tools for these genetic disorders have been developed. Polyglutamine disease research has successfully used interdisciplinary collaborative efforts, informative multiple mouse genetic models and advanced tools of pharmaceutical industry research to potentially serve as the prototype model of therapeutic research and development for rare neurodegenerative diseases.

Résumé:

RÉSUMÉ:

Depuis le début des années 1990, on a découvert qu’une expansion de répétitions de triplets d’ADN était la cause d’un nombre de plus en plus considérable de maladies neurologiques d’étiologie génétique. Un sousgroupe de cette grande famille de maladies génétiques possède une expansion d’un triplet CAG dans le cadre de lecture ouvert d’un exon codant. Cette expansion de l’ADN s’exprime au niveau de la protéine atteinte par une expansion de la séquence répétée d’un acide aminé, la glutamine, ce qui a donné lieu au terme de maladies à polyglutamines, terme qui s’applique à cette sous-famille de maladies. Jusqu‘à maintenant, ce phénomène a été observé dans neuf gènes différents en relation avec des maladies à polyglutamines dont la maladie de Huntington, la maladie de Machado-Joseph et l’amyotrophie spino-bulbaire ou maladie de Kennedy. La plupart des maladies à polyglutamines se classent au point de vue clinique parmi les ataxies spino-cérébelleuses. Nous discutons des découvertes récentes et des progrès de la recherche sur les maladies à polyglutamines et nous comparons ces différentes maladies qui ont un défaut génétique commun au point de vue biologie moléculaire. Nous traitons également de « drug design » pour une famille de maladies pour lesquelles plusieurs nouveaux outils de recherche ont été développés. La recherche sur les maladies à polyglutamines a bénéficié d’une collaboration interdisciplinaire et a utilisé avec succès plusieurs modèles génétiques de souris très informatifs ainsi que des outils de pointe de la recherche pharmaceutique et servira potentiellement de prototype en recherche et développement thérapeutique pour les maladies neurodégénératives rares.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 33 , Issue 3 , August 2006 , pp. 278 - 291
Copyright
Copyright © The Canadian Journal of Neurological 2006

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