Quantitative connection between polyglutamine aggregation kinetics and neurodegenerative process in patients with Huntington's disease.

Molecular Neurodegeneration
Keizo Sugaya, Shiro Matsubara

Abstract

Despite enormous progress in elucidating the biophysics of aggregation, no cause-and-effect relationship between protein aggregation and neurodegenerative disease has been unequivocally established. Here, we derived several risk-based stochastic kinetic models that assess genotype/phenotype correlations in patients with Huntington's disease (HD) caused by the expansion of a CAG repeat. Fascinating disease-specific aspects of HD include the polyglutamine (polyQ)-length dependence of both age at symptoms onset and the propensity of the expanded polyQ protein to aggregate. In vitro, aggregation of polyQ peptides follows a simple nucleated growth polymerization pathway. Our models that reflect polyQ aggregation kinetics in a nucleated growth polymerization divided aggregate process into the length-dependent nucleation and the nucleation-dependent elongation. In contrast to the repeat-length dependent variability of age at onset, recent studies have shown that the extent of expansion has only a subtle effect on the rate of disease progression, suggesting possible differences in the mechanisms underlying the neurodegenerative process. Using polyQ-length as an index, these procedures enabled us for the first time to establish a quanti...Continue Reading

References

Oct 29, 1993·Science·J T Coyle, P Puttfarcken
Dec 1, 1996·Archives of Neurology·E H AylwardJ Brandt
May 13, 1998·Brain : a Journal of Neurology·T KlockgetherJ Dichgans
Jul 19, 2000·Biochimica Et Biophysica Acta·M A SmithG Perry
Mar 17, 2001·Nature Reviews. Neuroscience·J F Gusella, M E MacDonald
Oct 24, 2001·Human Molecular Genetics·G ClarkeR R McInnes
Mar 13, 2002·Neurology·B P C van de WarrenburgH P H Kremer
Apr 18, 2002·Proceedings of the National Academy of Sciences of the United States of America·M F PerutzA Lesk
Aug 21, 2002·Proceedings of the National Academy of Sciences of the United States of America·Songming ChenRonald Wetzel
Aug 29, 2003·Science of Aging Knowledge Environment : SAGE KE·Douglas A GrayJohn Woulfe
Mar 18, 2004·Clinical Genetics·D R LangbehnUNKNOWN International Huntington's Disease Collaborative Group
Mar 5, 2005·Annals of Neurology·Bart P C van de WarrenburgBerry P H Kremer
Mar 8, 2005·Journal of Theoretical Biology·Geoff Clarke, Charles J Lumsden
Oct 6, 2005·Nature Reviews. Genetics·Jennifer R Gatchel, Huda Y Zoghbi
Oct 19, 2005·Proceedings of the National Academy of Sciences of the United States of America·Anusri M BhattacharyyaRonald Wetzel
Apr 21, 2006·The Journal of Biological Chemistry·Andrew M EllisdonStephen P Bottomley
May 16, 2006·Nature Chemical Biology·David W ColbyK Dane Wittrup
May 20, 2006·Nature Chemical Biology·Ronald Wetzel
Jul 11, 2006·Trends in Biochemical Sciences·James F Gusella, Marcy E MacDonald
Oct 19, 2006·Methods in Enzymology·Alexander P OsmandRonald Wetzel
Jan 25, 2007·Nature Reviews. Molecular Cell Biology·Christian Haass, Dennis J Selkoe
Mar 21, 2007·Nature Structural & Molecular Biology·Yoshitaka NagaiTatsushi Toda
Jul 7, 2007·Journal of Neurology, Neurosurgery, and Psychiatry·H H RuoccoF Cendes
Mar 10, 2009·Nature Structural & Molecular Biology·Ashwani K ThakurRonald Wetzel
Jun 3, 2009·Proceedings of the National Academy of Sciences of the United States of America·Yoko Nekooki-MachidaMotomasa Tanaka
Jul 11, 2009·Protein Engineering, Design & Selection : PEDS·Helen M Saunders, Stephen P Bottomley

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Citations

Nov 18, 2014·Frontiers in Cellular Neuroscience·Keizo Sugaya, Imaharu Nakano
Sep 6, 2017·Journal of Proteome Research·Virender SinghAshwani Kumar Thakur

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