Polyglutamine Expansion Mutation Yields a Pathological Epitope Linked to Nucleation of Protein Aggregate: Determinant of Huntington's Disease Onset

Keizo Sugaya,Akihiro Kawata,Hideaki Hayashi,Yasuhiro Kagamihara,Shiro Matsubara

doi:10.1371/journal.pone.0000635

Keizo Sugaya, Akihiro Kawata + Show 3 more

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https://doi.org/10.1371/journal.pone.0000635

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Journal: PloS one	Publication Date: Jul 25, 2007
Citations: 30	License type: CC BY 4.0

Affiliation: Tokyo Metropolitan Neurological Hospital

Abstract

Polyglutamine (polyQ) expansion mutation causes conformational, neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. These diseases are characterized by the aggregation of misfolded proteins, such as amyloid fibrils, which are toxic to cells. Amyloid fibrils are formed by a nucleated growth polymerization reaction. Unexpectedly, the critical nucleus of polyQ aggregation was found to be a monomer, suggesting that the rate-limiting nucleation process of polyQ aggregation involves the folding of mutated protein monomers. The monoclonal antibody 1C2 selectively recognizes expanded pathogenic and aggregate-prone glutamine repeats in polyQ diseases, including Huntington's disease (HD), as well as binding to polyleucine. We have therefore assayed the in vitro and in vivo aggregation kinetics of these monomeric proteins. We found that the repeat-length-dependent differences in aggregation lag times of variable lengths of polyQ and polyleucine tracts were consistently related to the integration of the length-dependent intensity of anti-1C2 signal on soluble monomers of these proteins. Surprisingly, the correlation between the aggregation lag times of polyQ tracts and the intensity of anti-1C2 signal on soluble monomers of huntingtin precisely reflected the repeat-length dependent age-of-onset of HD patients. These data suggest that the alterations in protein surface structure due to polyQ expansion mutation in soluble monomers of the mutated proteins act as an amyloid-precursor epitope. This, in turn, leads to nucleation, a key process in protein aggregation, thereby determining HD onset. These findings provide new insight into the gain-of-function mechanisms of polyQ diseases, in which polyQ expansion leads to nucleation rather than having toxic effects on the cells.

Highlights

To date, nine polyglutamine diseases have been identified: Huntington’s disease (HD), spinal and bulbar muscular atrophy, spinocerebellar ataxia and dentatorubral-pallidoluysian atrophy, each of which results from an abnormally increased number of residues in a polyQ tract of the corresponding gene product [1]
Despite the complexity of the cellular environment, including degradation and transport processes capable of partitioning proteins into different molecular forms and compartments, and the presence of chaperones that modulate polyQ aggregation and cellular toxicity [15], [16], our results strongly suggest that the pathological epitope detected by 1C2 and its link to nucleation are critical in determining HD onset
Since the discovery of the androgen receptor gene mutation in the polyQ diseases spinal and bulbar muscular atrophy [20], the increased knowledge of various polyQ diseases has shown that the unifying pathogenic mechanism of these diseases and of their characteristic features arises from the expansion of polyQ itself [1], [4], [12], [21]

Summary

Introduction

Nine polyglutamine (polyQ) diseases have been identified: Huntington’s disease (HD), spinal and bulbar muscular atrophy, spinocerebellar ataxia (types 1, 2, 3, 6, 7, and 12) and dentatorubral-pallidoluysian atrophy, each of which results from an abnormally increased number of residues in a polyQ tract of the corresponding gene product [1]. Since the increased length of polyQ proteins has been associated with earlier onset and more severe manifestation of the disease state, expansion of the polyQ tract is thought to be the key causal element of the disease process [4]. PolyQ diseases have been found to belong to a wide range of neurodegenerative diseases associated with protein misfolding and aggregation, including Alzheimer’s, prion and Parkinson’s diseases [5], [6]. In many of these conditions, protein deposition involves the formation of amyloid fibrils, and polyQ aggregates show many of the attributes of amyloid [7], [8]. Amyloid fibril growth is considered to be controlled by nucleated growth polymerization, a two-stage process consisting of the energetically unfavorable formation of a nucleus, followed by efficient elongation of the nucleus via sequential additions of monomer [9], [10]

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