The Role of Protein Misfolding in the Pathogenesis of Human Diseases

Ellisdon, Andrew M.; Bottomley, Stephen P.

doi:10.1080/15216540410001674003

Cited by 24 publications

(20 citation statements)

References 30 publications

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“…Various types of intraneuronal aggregates, including nuclear inclusions, of the poly(Q) protein in question are also evident upon post-mortem analysis (20 -22). These observations, among others, suggest that poly(Q) diseases are conformational diseases, in which toxicity is linked to the ability of the protein to self-associate and form aggregates (23)(24)(25)(26)(27).…”

mentioning

confidence: 99%

The Two-stage Pathway of Ataxin-3 Fibrillogenesis Involves a Polyglutamine-independent Step

Ellisdon¹,

Thomas

Bottomley

2006

Journal of Biological Chemistry

157

196

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The aggregation of ataxin-3 is associated with spinocerebellar ataxia type 3, which is characterized by the formation of intraneuronal aggregates. However, the mechanism of aggregation is currently not well understood. Ataxin-3 consists of a folded Josephin domain followed by two ubiquitin-interacting motifs and a C-terminal polyglutamine tract, which in the non-pathological form is less than 45 residues in length. We demonstrate that ataxin-3 with 64 glutamines (at(Q64)) undergoes a two-stage aggregation. The first stage involves formation of SDS-soluble aggregates, and the second stage results in formation of SDS-insoluble aggregates via the poly(Q) region. Both these first and second stage aggregates display typical amyloid-like characteristics. Under the same conditions at(Q15) and at(QHQ) undergo a single step aggregation event resulting in SDS-soluble aggregates, which does not involve the polyglutamine tract. These aggregates do not convert to the SDSinsoluble form. These observations demonstrate that ataxin-3 has an inherent capacity to aggregate through its non-polyglutamine domains. However, the presence of a pathological length polyglutamine tract introduces an additional step resulting in formation of a highly stable amyloid-like aggregate.Ataxin-3 is a 42-kDa multi-domain protein consisting of an N-terminal Josephin domain, two ubiquitin-interacting motifs, which are situated next to a polymorphous C-terminal polyglutamine (poly(Q)) 3 tract (1, 2). Ataxin-3 functions as a de-ubiquitinating enzyme (3, 4) and binds polyubiquitin chains through the ubiquitin-interacting motifs (5-8). Expansion of the poly(Q) tract beyond 45 residues causes spinocerebellar ataxia type 3 (SCA3) also known as Machado-Joseph disease (9, 10). Similar dynamic expansion of poly(Q) tracts within various other proteins causes a further eight autosomally dominant neurodegenerative diseases, collectively termed poly(Q) diseases (2, 11).Several key observations have led to the conclusion that poly(Q) diseases originate via a toxic gain of function, mediated by poly(Q) tract expansion. Firstly, the manifestation of each poly(Q) disease is directly reliant on a threshold length of consecutive glutamine residues. In all of the diseases, except for SCA6, this threshold is remarkably similar with a tract length in excess of 40 residues associated with disease onset (2).Secondly, there is a non-linear correlation between an increasing glutamine tract length and an earlier age of disease onset (12). Thirdly, different proteins involved in each of the various poly(Q) diseases share no sequence homology except the presence of the glutamine tract (13).Various studies have suggested that this toxic gain of function is causally linked to aberrant protein aggregation mediated by the extended poly(Q) tract (14). In vitro studies have shown that poly(Q) peptides, fragments, and proteins can form amyloid-like fibrillar aggregates and that the aggregation rate increases with increasing glutamine tract length (15)(16)(17)(18)(19). Various types of ...

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confidence: 99%

The Two-stage Pathway of Ataxin-3 Fibrillogenesis Involves a Polyglutamine-independent Step

Ellisdon¹,

Thomas

Bottomley

2006

Journal of Biological Chemistry

157

196

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“…The mechanisms of polyglutamine toxicity are still largely unelucidated; however, an increasing number of reports indicate that the polyglutamine disorders belong to a wider range of diseases that associated with protein misfolding, including Alzheimer's disease, Parkinson's disease, and a range of amyloidoses (11)(12)(13)(14). All of these disorders involve the formation and deposition of protein aggregates within diseased tissues and/or cells.…”

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confidence: 99%

Polyglutamine Expansion in Ataxin-3 Does Not Affect Protein Stability

Chow

Ellisdon

Cabrita

et al. 2004

Journal of Biological Chemistry

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Polyglutamine proteins that cause neurodegenerative disease are known to form proteinaceous aggregates, such as nuclear inclusions, in the neurons of affected patients. Although polyglutamine proteins have been shown to form fibrillar aggregates in a variety of contexts, the mechanisms underlying the aberrant conformational changes and aggregation are still not well understood. In this study, we have investigated the hypothesis that polyglutamine expansion in the protein ataxin-3 destabilizes the native protein, leading to the accumulation of a partially unfolded, aggregation-prone intermediate. To examine the relationship between polyglutamine length and native state stability, we produced and analyzed three ataxin-3 variants containing 15, 28, and 50 residues in their respective glutamine tracts. At pH 7.4 and 37°C, Atax3(Q50), which lies within the pathological range, formed fibrils significantly faster than the other proteins. Somewhat surprisingly, we observed no difference in the acid-induced equilibrium and kinetic un/folding transitions of all three proteins, which indicates that the stability of the native conformation was not affected by polyglutamine tract extension. This has led us to reconsider the mechanisms and factors involved in ataxin-3 misfolding, and we have developed a new model for the aggregation process in which the pathways of un/folding and misfolding are distinct and separate. Furthermore, given that native state stability is unaffected by polyglutamine length, we consider the possible role and influence of other factors in the fibrillization of ataxin-3.

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“…Failure to fold to into its correct structure limits of abrogates the protein's ability to perform the biological roles for which it was produced [35]. Not only does the aggregation of folding intermediates strips the cell of an important resource, the presence of the aggregate themselves can have dire consequence and results in a wide range of disease such as described in the Table 1.…”

Section: Amyloidosis Diseasesmentioning

confidence: 99%

Review: structure of amyloid fibril in diseases

Ghahghaei¹,

Faridi²

2009

JBiSE

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Tissue deposition of normally soluble proteins, or their fragments, as insoluble amyloid fibrils causes both acquired and hereditary systemic amyloidoses, which is usually fatal. Amyloid is associated with serious diseases such as Alzheimer's disease, type 2 diabetes, Parkinson's Disease, Huntington's Disease, cancer and the transmissible spongiform encephalopathies. Information concerning the structure and mechanism of formation of fibrils in these diseases is critical for understanding the process of pathology of the amyloidoses and to the development of more effective therapeutic agents that target the underlying disease mechanisms. Structural models have been made using information from a wide variety of techniques, including electron microscopy, X-ray diffraction, solid state NMR, and Congo red and CD spectroscopy. Although each type of amyloidosis is characterised by a specific amyloid fibril protein, the deposits share pathognomonic histochemical properties and the structural morphology of all amyloid fibrils is very similar. In fact, the structural similarity that defines amyloid fibres exists principally at the level of β-sheet folding of the polypeptides within the protofilament, while the different types vary in the supramolecular assembly of their protofilaments.

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The Role of Protein Misfolding in the Pathogenesis of Human Diseases

Cited by 24 publications

References 30 publications

The Two-stage Pathway of Ataxin-3 Fibrillogenesis Involves a Polyglutamine-independent Step

The Two-stage Pathway of Ataxin-3 Fibrillogenesis Involves a Polyglutamine-independent Step

Polyglutamine Expansion in Ataxin-3 Does Not Affect Protein Stability

Review: structure of amyloid fibril in diseases

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