title: Proteomic analysis of the human brain in Huntington's Disease indicates pathogenesis by molecular processes linked to other neurodegenerative diseases and to type-2 diabetes.
abstract: BACKGROUND
  Huntington's disease (HD) is a neurodegenerative disorder in which the aetiological defect is inherited or spontaneous mutation in the HTT gene, which alters the structure of the corresponding huntingtin protein and initiates a pathogenetic cascade that ultimately leads to or causes dementia.
  
  
  OBJECTIVE
  Here our main objective was to elucidate further the pathogenic processes that underlie neurodegeneration in HD.
  
  
  METHODS
  By using two-dimensional gel electrophoresis we performed a proteomic case-control study of two brain regions in post-mortem human tissue from seven well-characterized HD patients and eight matched controls.
  
  
  RESULTS
  In the middle frontal gyrus we identified twenty-two differentially-expressed proteins whereas by contrast in visual cortex only seven were altered. Twenty of these proteins have not to our knowledge been associated with the pathogenesis of HD before although all functional families implicated have previously been linked to other neurodegenerative diseases. Most of the proteins identified play roles in cell stress responses, apoptosis, metabolic regulation linked to type-2 diabetes, the ubiquitin-proteasome system, or protein trafficking/endocytosis.
  
  
  CONCLUSIONS
  We propose that HTT mutations lead to or cause functional impairment of these pathways and that simultaneous restoration of their functions by targeted pharmacotherapy could ameliorate the signs and symptoms of HD. These studies provide a unique illustration of the interlinked disease processes that underpin/contribute to the pathogenesis of neurodegeneration in a genetically-mediated disorder of protein structure, and provide a signpost towards the design of new therapeutic interventions.
authors: School of Biological Sciences, University of Auckland, Auckland, New Zealand.
authors: Sarah J
authors: SJ
authors: Schönberger
authors: School of Biological Sciences, University of Auckland, Auckland, New Zealand Centre for Brain Research, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand.
authors: Dina
authors: D
authors: Jezdic
authors: Centre for Brain Research, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand.
authors: Richard L M
authors: RL
authors: Faull
authors: School of Biological Sciences, University of Auckland, Auckland, New Zealand Faculty of Science, Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand Centre for Brain Research, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand Faculty of Medical and Human Sciences, Institute of Human Development, The University of Manchester, and Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, UK.
authors: Garth J S
authors: GJ
authors: Cooper
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010449:Peptide Mapping; D040901:Proteomics
keywords: Dementia; copper; experimental therapeutics; human brain; metabolic stress; oxidative stress; type-2 diabetes