Brain Advance Access originally published online on April 13, 2006
Brain 2006 129(6):1357-1370; doi:10.1093/brain/awl081
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Review Article |
Molecular pathogenesis of spinocerebellar ataxias
1 Institute of Child Health, University College London London, UK 2 Department of Molecular Neuroscience, Institute of Neurology, University College London London, UK
Correspondence to: Antoni Matilla Dueñas, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK and Paola Giunti, Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, WCIN 3BG. E-mail: A.Matilla{at}ich.ucl.ac.uk
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.
Key Words: spinocerebellar ataxias; cerebellum; neurodegenerative disorders; neurodegenerative mechanisms; therapy
Abbreviations: ADCA, autosomal dominant spinocerebellar ataxia; CAG, DNA sequence coding for glutamine; DRPLA, dentatorubral pallidoluysian atrophy; ER, endoplasmic reticulum; FGF14, fibroblast growth factor 14; HDACs, histone deacetylases; KCNC3, potassium voltage-gated channel subfamily C member 3; PP2, protein phosphatase 2 (formerly 2A); PRKCG, protein kinase C, gamma; Q, glutamine; SCA, spinocerebellar ataxia; SPTBN2, beta-III spectrin; TBP, TATA box binding protein; UPS, ubiquitin-dependent proteasome system
Received December 7, 2005. Revised February 28, 2006. Accepted March 2, 2006.
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