Polyglutamine gene function and dysfunction in the ageing brain
Polyglutamine gene function and dysfunction in the ageing brain
The coordinated regulation of gene expression and protein interactions determines how mammalian nervous systems develop and retain function and plasticity over extended periods of time such as a human life span. By studying mutations that occur in a group of genes associated with chronic neurodegeneration, the polyglutamine (polyQ) disorders, it has emerged that CAG/glutamine stretches play important roles in transcriptional regulation and protein–protein interactions.
However, it is still unclear what the many structural and functional roles of CAG and other low-complexity sequences in eukaryotic genomes are, despite being the most commonly shared peptide fragments in such proteomes. In this review we examine the function of genes responsible for at least 10 polyglutamine disorders in relation to the nervous system and how expansion mutations lead to neuronal dysfunction, by particularly focusing on Huntington's disease (HD).
We argue that the molecular and cellular pathways that turn out to be dysfunctional during such diseases, as a consequence of a CAG expansion, are also involved in the ageing of the central nervous system. These are pathways that control protein degradation systems (including molecular chaperones), axonal transport, redox-homeostasis and bioenergetics. CAG expansion mutations confer novel properties on proteins that lead to a slow-progressing neuronal pathology and cell death similar to that found in other age-related conditions such as Alzheimer's and Parkinson's diseases.
ageing, polyglutamine, huntington's disease, central nervous system, protein misfolding, neurodegeneration
507-521
Hands, Sarah
a558692f-fad3-4d9c-ada1-abd95946512c
Sinadinos, Christopher
fcc3580b-a0db-4060-91b7-8ce102a0af69
Wyttenbach, Andreas
05019897-52b1-4bb6-b259-5d51abae7540
August 2008
Hands, Sarah
a558692f-fad3-4d9c-ada1-abd95946512c
Sinadinos, Christopher
fcc3580b-a0db-4060-91b7-8ce102a0af69
Wyttenbach, Andreas
05019897-52b1-4bb6-b259-5d51abae7540
Hands, Sarah, Sinadinos, Christopher and Wyttenbach, Andreas
(2008)
Polyglutamine gene function and dysfunction in the ageing brain.
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1779 (8), .
(doi:10.1016/j.bbagrm.2008.05.008).
Abstract
The coordinated regulation of gene expression and protein interactions determines how mammalian nervous systems develop and retain function and plasticity over extended periods of time such as a human life span. By studying mutations that occur in a group of genes associated with chronic neurodegeneration, the polyglutamine (polyQ) disorders, it has emerged that CAG/glutamine stretches play important roles in transcriptional regulation and protein–protein interactions.
However, it is still unclear what the many structural and functional roles of CAG and other low-complexity sequences in eukaryotic genomes are, despite being the most commonly shared peptide fragments in such proteomes. In this review we examine the function of genes responsible for at least 10 polyglutamine disorders in relation to the nervous system and how expansion mutations lead to neuronal dysfunction, by particularly focusing on Huntington's disease (HD).
We argue that the molecular and cellular pathways that turn out to be dysfunctional during such diseases, as a consequence of a CAG expansion, are also involved in the ageing of the central nervous system. These are pathways that control protein degradation systems (including molecular chaperones), axonal transport, redox-homeostasis and bioenergetics. CAG expansion mutations confer novel properties on proteins that lead to a slow-progressing neuronal pathology and cell death similar to that found in other age-related conditions such as Alzheimer's and Parkinson's diseases.
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Published date: August 2008
Keywords:
ageing, polyglutamine, huntington's disease, central nervous system, protein misfolding, neurodegeneration
Identifiers
Local EPrints ID: 145333
URI: http://eprints.soton.ac.uk/id/eprint/145333
ISSN: 1874-9399
PURE UUID: bc4daad6-6f14-4bec-ae08-e2fb6154ea0e
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Date deposited: 19 Apr 2010 08:34
Last modified: 14 Mar 2024 00:50
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Contributors
Author:
Sarah Hands
Author:
Christopher Sinadinos
Author:
Andreas Wyttenbach
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