TAILIEUCHUNG - Báo cáo khoa học: Huntington’s disease: revisiting the aggregation hypothesis in polyglutamine neurodegenerative diseases

After the successful cloning of the first gene for a polyglutamine disease in 1991, the expanded polyglutamine tract in the nine polyglutamine disease proteins became an obvious therapeutic target. Early hypotheses were that misfolded, precipitated protein could be a universal pathogenic mechanism. However, new data are accumulating on Huntington’s disease and other polyglutamine diseases that appear to contradict the toxic aggregate hypothesis. | ễFEBS Journal MINIREVIEW Huntington s disease revisiting the aggregation hypothesis in polyglutamine neurodegenerative diseases Ray Truant Randy Singh Atwal Carly Desmond Lise Munsie and Thu Tran Department of Biochemistry and BiomedicalSciences McMaster University Hamilton Canada Keywords huntingtin Huntington s disease polyglutamine protein aggregation protein misfolding Spinocerebellar ataxia Correspondence R. Truant Department of Biochemistry and BiomedicalSciences McMaster University 1200 Main Street West HSC 4H24A Hamilton Ontario L8N3Z5 Canada Fax 1 905 522 9033 Tel 1 905 525 9140 ext. 22450 E-mail truantr@ Website http After the successful cloning of the first gene for a polyglutamine disease in 1991 the expanded polyglutamine tract in the nine polyglutamine disease proteins became an obvious therapeutic target. Early hypotheses were that misfolded precipitated protein could be a universal pathogenic mechanism. However new data are accumulating on Huntington s disease and other polyglutamine diseases that appear to contradict the toxic aggregate hypothesis. Recent data suggest that the toxic species of protein in these diseases may be soluble mutant conformers and that the protein context of expanded polyglutamine is critical to understanding disease specificity. Here we discuss recent publications that define other important therapeutic targets for polyglutamine-mediated neurodegeneration related to the context of the expanded polyglutamine tract in the disease protein. Received 1 March 2008 revised 21 April 2008 accepted 12 May 2008 doi The toxic aggregate hypothesis in polyglutamine diseases With the identification of expanded CAG repeats of the X-linked spinal and bulbar muscular atrophy SBMA or Kennedy s disease gene at the androgen receptor in 1991 1 followed by the Huntington s disease HD gene in 1993 2 and the cloning of the spinocerebellar ataxia type 1 gene 3 the expanded .

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