Amyloid-like inclusions in Huntington’s disease

McGowan, Daniel; Roon-Mom, Willeke van; Holloway, Hilary; Bates, Gillian P.; Mangiarini, Laura; Cooper, Garth J. S.; Faull, Richard L.M.; Snell, Russell G.

doi:10.1016/s0306-4522(00)00391-2

Cited by 94 publications

(54 citation statements)

References 13 publications

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“…Although the role of protein aggregates in the pathogenic process is not clear, protein aggregation itself is a hallmark of the majority of neurodegenerative diseases, including the diseases associated with polyglutamine repeats, Alzheimer disease, amyotrophic lateral sclerosis (ALS), prion diseases and some forms of Parkinson disease 39 . Amyloid-like structures in brain of individuals with Huntington disease 40 suggest parallels to other amyloid-associated diseases, such as Alzheimer and prion diseases. A potential causal role for aggregation in ALS has been suggested by the inability of increased expression of wildtype Sod1 in a mouse ALS model to slow disease progression or pathology 41 .…”

Section: Discussionmentioning

confidence: 99%

A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila

et al. 2002

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Section: Discussionmentioning

confidence: 99%

A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila

et al. 2002

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“…To test whether amyloidlike inclusions like those found in postmortem brains of HD patients (McGowan et al, 2000) can be detected in the brains of Tet/HD94 mice, we performed thioflavin-S staining on brain sections from Tet/HD94 mice at different ages (initially, 10 and 17 months). Positive thioflavin-S inclusions were detected in cortex, striatum, and hippocampus of 17-month-old Tet/HD94 mice (Fig.…”

Section: Irreversible Amyloid-like Inclusions In the Brain Of Tet/hd9mentioning

confidence: 99%

Full Motor Recovery Despite Striatal Neuron Loss and Formation of Irreversible Amyloid-Like Inclusions in a Conditional Mouse Model of Huntington's Disease

Dı́az-Hernández

Torres-Peraza²,

Salvatori-Abarca³

et al. 2005

J. Neurosci.

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The primary mechanism responsible for Huntington's disease remains unknown. Postulated early pathogenic events include the following: impaired protein folding, altered protein degradation, mitochondrial dysfunction, and transcriptional dysregulation. Although related therapies can delay disease progression in mouse models, they target downstream and probably indirect effects of mutanthuntingtin expression. Accordingly, in case they prove beneficial in humans, they might only palliate some aspects of disease. Our previous studies in the Tet/HD94 conditional model and the recently reported efficacy of RNA interference against mutant huntingtin in another mouse model support silencing mutant-huntingtin expression as a valid therapeutic approach that has the advantage of targeting toxicity at its root. Here, we address whether gene silencing can still be beneficial in the late stages of disease with detectable striatal neuron loss. Stereological analysis was applied to determine an age at which Tet/HD94 mice show a decrease in the number of striatal neurons. Then, progression of neuropathology and motor phenotype were analyzed in mice that were allowed to continue expressing mutant huntingtin and in mice that no longer expressed it. Neuronal loss did not revert in gene-off mice, but the additional loss that takes place in gene-on mice was prevented. The total number of huntingtin-containing inclusions dramatically reverted, but a small fraction of inclusions positive for the amyloid dye thioflavin-S remained. Interestingly, despite a 20% decrease in striatal neurons and the presence of amyloid-like irreversible inclusions, gene-off mice fully recover from their motor deficit, thus ruling out amyloid-like huntingtin inclusions as the main toxic species and suggesting that gene-silencing therapies might work in late stages of disease.

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“…In the case of polyglutamine diseases, the formation of NIs and the presence of proteasomal proteins in aggregates suggest that similar protein misfolding processes take place. In vivo, NIs display a range of morphologies, including granular, fibrillar, and amorphous forms (8,10,(16)(17)(18). In vitro, expanded forms of polyglutamine-containing proteins and peptides have been shown to form fibrils very readily (17,(19)(20)(21)(22).…”

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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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Amyloid-like inclusions in Huntington’s disease

Cited by 94 publications

References 13 publications

A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila

A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila

Full Motor Recovery Despite Striatal Neuron Loss and Formation of Irreversible Amyloid-Like Inclusions in a Conditional Mouse Model of Huntington's Disease

Polyglutamine Expansion in Ataxin-3 Does Not Affect Protein Stability

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