title: Quantitative connection between polyglutamine aggregation kinetics and neurodegenerative process in patients with Huntington's disease.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  Using polyQ-length as an index, these procedures enabled us for the first time to establish a quantitative connection between aggregation kinetics and disease process, including onset and the rate of progression. Although the complexity of disease process in HD, the time course of striatal neurodegeneration can be precisely predicted by the mathematical model in which neurodegeneration occurs by different mechanisms for the initiation and progression of disease processes. Nucleation is sufficient to initiate neuronal loss as a series of random events in time. The stochastic appearance of nucleation in a cell population acts as the constant risk of neuronal cell damage over time, while elongation reduces the risk by nucleation in proportion to the increased extent of the aggregates during disease progression.
  
  
  CONCLUSIONS
  Our findings suggest that nucleation is a critical step in gaining toxic effects to the cell, and provide a new insight into the relationship between polyQ aggregation and neurodegenerative process in HD.
authors.affiliation: Department of Neurology, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo, Japan. keizo_sugaya@member.metro.tokyo.jp
authors.forename: Keizo
authors.initials: K
authors.lastname: Sugaya
authors.forename: Shiro
authors.initials: S
authors.lastname: Matsubara
mesh_terms: D017668:Age of Onset; D016923:Cell Death / Q000502:physiology; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D007700:Kinetics; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*
chemical_list: D010455:Peptides; C097188:polyglutamine