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Brain Advance Access published online on April 13, 2006
Brain, doi:10.1093/brain/awl081
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© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received December 7, 2005
Revised February 28, 2006
Accepted March 2, 2006

Article

Molecular pathogenesis of spinocerebellar ataxias

Antoni Matilla Dueñas 1 *, Robert Goold 1, and Paola Giunti 2

1 Institute of Child Health, University College London, London, UK
2 Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK

* To whom correspondence should be addressed.
Antoni Matilla Dueñas, E-mail: A.Matilla{at}ich.ucl.ac.uk


  Abstract

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases, clinically and genetically heterogeneous, characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its afferent and efferent connections. Despite a well-described clinical and pathological phenotype, the molecular and cellular events that underlie neurodegeneration are still poorly understood. Compelling evidence points to major aetiological roles for interference with transcriptional regulation, protein aggregation and clearance, the ubiquitin-proteasome system and alterations of calcium homeostasis in the neuronal loss observed during the neurodegenerative process. But novel molecular routes that might be disrupted during disease progression are also being identified. These pathways could act independently or, more likely, interact and enhance each other, triggering the accumulation of cellular damage that eventually leads to dysfunction and, ultimately, the demise of neurons through a series of multiple events. This suggests that simultaneous targeting of several pathways might be therapeutically necessary to prevent neurodegeneration and preserve neuronal function. Understanding how dysregulation of these pathways mediates disease progression is leading to the establishment of effective therapeutic strategies in vivo, which may prove beneficial in the treatment of SCAs. Herein, we review the latest evidence for the proposed molecular processes to the pathogenesis of dominantly inherited spinocerebellar ataxias and the current therapeutic strategies.

Keywords: spinocerebellar ataxias; cerebellum; neurodegenerative disorders; neurodegenerative mechanisms; therapy.
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