title: Insights from cerebellar transcriptomic analysis into the pathogenesis of ataxia.
abstract: OBJECTIVE
  The core clinical and neuropathological feature of the autosomal dominant spinocerebellar ataxias (SCAs) is cerebellar degeneration. Mutations in the known genes explain only 50% to 60% of SCA cases. To date, no effective treatments exist, and the knowledge of drug-treatable molecular pathways is limited. The examination of overlapping mechanisms and the interpretation of how ataxia genes interact will be important in the discovery of potential disease-modifying agents.
  
  
  OBJECTIVE
  To address the possible relationships among known SCA genes, predict their functions, identify overlapping pathways, and provide a framework for candidate gene discovery using whole-transcriptome expression data.
  
  
  METHODS
  We have used a systems biology approach based on whole-transcriptome gene expression analysis. As part of the United Kingdom Brain Expression Consortium, we analyzed the expression profile of 788 brain samples obtained from 101 neuropathologically healthy individuals (10 distinct brain regions each). Weighted gene coexpression network analysis was used to cluster 24 SCA genes into gene coexpression modules in an unsupervised manner. The overrepresentation of SCA transcripts in modules identified in the cerebellum was assessed. Enrichment analysis was performed to infer the functions and molecular pathways of genes in biologically relevant modules.
  
  
  METHODS
  Molecular functions and mechanisms implicating SCA genes, as well as lists of relevant coexpressed genes as potential candidates for novel SCA causative or modifier genes.
  
  
  RESULTS
  Two cerebellar gene coexpression modules were statistically enriched in SCA transcripts (P = .021 for the tan module and P = 2.87 × 10-5 for the light yellow module) and contained established granule and Purkinje cell markers, respectively. One module includes genes involved in the ubiquitin-proteasome system and contains SCA genes usually associated with a complex phenotype, while the other module encloses many genes important for calcium homeostasis and signaling and contains SCA genes associated mostly with pure ataxia.
  
  
  CONCLUSIONS
  Using normal gene expression in the human brain, we identified significant cell types and pathways in SCA pathogenesis. The overrepresentation of genes involved in calcium homeostasis and signaling may indicate an important target for therapy in the future. Furthermore, the gene networks provide new candidate genes for ataxias or novel genes that may be critical for cerebellar function.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, England.
authors.forename: Conceição
authors.initials: C
authors.lastname: Bettencourt
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, England2Department of Medical and Molecular Genetics, King's College London, London, England.
authors.forename: Mina
authors.initials: M
authors.lastname: Ryten
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Forabosco
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, England.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schorge
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, England.
authors.forename: Joshua
authors.initials: J
authors.lastname: Hersheson
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, England.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, England.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D002526:Cerebellar Diseases / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000209:etiology* / Q000235:genetics*; D014015:Tissue Banks