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Modeling the Polyglutamine Aggregation Pathway in Huntington’s Disease: From Basic Studies to Clinical Applications

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Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease

Part of the book series: Subcellular Biochemistry ((SCBI,volume 65))

Abstract

Huntington’s disease (HD) is among the polyglutamine (polyQ) disorders, which are caused by expansion of CAG-trinucleotide repeats. These disorders share common characteristics, and have thus long been thought to have a unifying pathogenic mechanism resulting from polyQ expansion. However, this scenario has recently become more complex, as studies have found multiple pathways for the assembly of disease-related polyQ protein aggregates that differ in both structure and toxicity. There are fascinating disease-specific aspects of the polyQ disorders, including the repeat-length dependence of both clinical features and the propensity of the expanded polyQ protein to aggregate. Such aggregation kinetics have proven useful in explaining the disease process. This chapter describes two risk-based stochastic kinetic models, the cumulative-damage and one-hit models, that describe genotype-phenotype correlations in patients with polyQ diseases and reflect alternative pathways of polyQ aggregation. Using repeat-length as an index, several models explore the quantitative connection between aggregation kinetics and clinical data from HD patients. The correlations between CAG repeat-length and age-of-onset are re-evaluated, and the rate of disease progression (as assessed by clinical measures and longitudinal imaging studies of brain structure) are surveyed. Finally, I present a mathematical model by which the time course of neurodegeneration in HD can be precisely predicted, and discuss the association of the models with the major controversies about HD pathogenesis.

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Abbreviations

HD:

Huntington’s Disease

polyQ:

Polyglutamine

htt:

huntingtin

SCA:

Spino-Cerebellar Ataxia

SBMA:

spinal and Bulbar Muscular Atrophy

DRPLA:

Dentatorubral-Pallidoluysian Atrophy

QNE:

Quantified Neurological Examination

UPS:

Ubiquitin-Proteasome System

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  1. Department of Neurology, Tokyo Metropolitan Neurological Hospital, 2-6-1 Musashidai, 183-0042, Fuchu, Tokyo, Japan

    Keizo Sugaya

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  1. Inst. of Zoology, University of Mainz, Becherweg 6, Mainz, 55099, Germany

    J. Robin Harris

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Sugaya, K. (2012). Modeling the Polyglutamine Aggregation Pathway in Huntington’s Disease: From Basic Studies to Clinical Applications. In: Harris, J. (eds) Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease. Subcellular Biochemistry, vol 65. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5416-4_15

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