Huntington’s disease cerebrospinal fluid seeds aggregation of mutant huntingtin

Tan, Zhiqun; Dai, Wei; Erp, Theo G.M. van; Overman, Julia; Demuro, Angelo; Digman, Michelle A.; Hatami, Asa; Albay, Ricardo; Sontag, Emily M.; Potkin, Katya T; Ling, Shuo-Chien; Macciardi, Fabìo; Bunney, W. E.; Long, Jeffrey D.; Paulsen, Jane S.; Ringman, John M.; Parker, Ian; Glabe, Charles G.; Thompson, Leslie M.; Chiu, Wah; Potkin, Steve

doi:10.1038/mp.2015.81

Cited by 48 publications

(44 citation statements)

References 42 publications

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“…CSF has recently been associated with seeding aggregation of mutant Huntingtin,35 and various components have been posited for use as clinical biomarkers 36. The EBM then predicts changes in the amygdala, optic chiasm, and third ventricle.…”

Section: Discussionmentioning

confidence: 99%

An image‐based model of brain volume biomarker changes in Huntington's disease

Wijeratne

Young

Oxtoby

et al. 2018

Ann Clin Transl Neurol

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ObjectiveDetermining the sequence in which Huntington's disease biomarkers become abnormal can provide important insights into the disease progression and a quantitative tool for patient stratification. Here, we construct and present a uniquely fine‐grained model of temporal progression of Huntington's disease from premanifest through to manifest stages.MethodsWe employ a probabilistic event‐based model to determine the sequence of appearance of atrophy in brain volumes, learned from structural MRI in the Track‐HD study, as well as to estimate the uncertainty in the ordering. We use longitudinal and phenotypic data to demonstrate the utility of the patient staging system that the resulting model provides.ResultsThe model recovers the following order of detectable changes in brain region volumes: putamen, caudate, pallidum, insula white matter, nonventricular cerebrospinal fluid, amygdala, optic chiasm, third ventricle, posterior insula, and basal forebrain. This ordering is mostly preserved even under cross‐validation of the uncertainty in the event sequence. Longitudinal analysis performed using 6 years of follow‐up data from baseline confirms efficacy of the model, as subjects consistently move to later stages with time, and significant correlations are observed between the estimated stages and nonimaging phenotypic markers.InterpretationWe used a data‐driven method to provide new insight into Huntington's disease progression as well as new power to stage and predict conversion. Our results highlight the potential of disease progression models, such as the event‐based model, to provide new insight into Huntington's disease progression and to support fine‐grained patient stratification for future precision medicine in Huntington's disease.

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Section: Discussionmentioning

confidence: 99%

An image‐based model of brain volume biomarker changes in Huntington's disease

Wijeratne

Young

Oxtoby

et al. 2018

Ann Clin Transl Neurol

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“…Cellular work has previously shown that it is possible to seed the formation of puncta using polyQ proteins. 20,27 Furthermore, Serpionov and co-workers showed that HTTQ25 aggregation can be seeded and in turn seed the aggregation of other Q/N-rich proteins in yeast. 28 Our data show that for HTT ex1 this is a direct seeding effect in which the seed structure is almost entirely reproduced by the new fibril that is formed.…”

Section: Discussionmentioning

confidence: 99%

Formation and Structure of Wild Type Huntingtin Exon-1 Fibrils

et al. 2017

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The fact that the heritable neurodegenerative disorder Huntington’s Disease (HD) is autosomal dominant means that there is one wild type and one mutant allele in most HD patients. The CAG repeat expansion in the exon 1 of the protein huntingtin (HTTex1) that causes the disease, leads to the formation of HTT fibrils in vitro and vivo. An important question for understanding the molecular mechanism of HD is which role wild type HTT plays for the formation, propagation, and structure of these HTT fibrils. Here we report that fibrils of mutant HTTex1 are able to seed the aggregation of wild type HTTex1 into amyloid fibrils which in turn can seed the fibril formation of mutant HTTex1. Solid-state NMR and EPR data showed that wild type HTTex1 fibrils closely resemble the structure of mutant fibrils, with small differences indicating a less extended fibril core. These data suggest that wild type fibrils can faithfully perpetuate the structure of mutant fibrils in HD. However, wild type HTTex1 monomers have a much higher equilibrium solubility compared to mutant HTTex1 and only a small fraction incorporates into fibrils.

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“…87 Furthermore, aggregates isolated from several HD transgenic mouse models seed the aggregation of pure polyQ peptides in vitro , 88 and seeding of mutant htt aggregation is also induced by cerebrospinal fluid from transgenic rats and human HD patients. 89 Aggregates of synthetic htt exon1-like peptides grown under conditions that promote different aggregation pathways have varying abilities to seed further aggregation. 38 This observation is interesting considering that, in a Drosophila model, polyQ amyloids formed in older flies more efficiently seeded in vitro aggregation than those derived from younger flies, 90 suggesting that aggregates formed in flies vary in their biophysical properties and perhaps aggregation mechanism as a function of fly age.…”

Section: Polyq-mediated Protein Aggregation Is a Complex Processmentioning

confidence: 99%

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

et al. 2017

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Several hereditary neurological and neuromuscular diseases are caused by an abnormal expansion of trinucleotide repeats. To date, there have been ten of these trinucleotide repeat disorders associated with an expansion of the codon CAG encoding glutamine (Q). For these polyglutamine (polyQ) diseases, there is a critical threshold length of the CAG repeat required for disease, and further expansion beyond this threshold is correlated with age of onset and symptom severity. PolyQ expansion in the translated proteins promotes their self-assembly into a variety of oligomeric and fibrillar aggregate species that accumulate into the hallmark proteinaceous inclusion bodies associated with each disease. Here, we review aggregation mechanisms of proteins with expanded polyQ-tracts, structural consequences of expanded polyQ ranging from monomers to fibrillar aggregates, the impact of protein context and post translational modifications on aggregation, and a potential role for lipids membranes in aggregation. As the pathogenic mechanisms that underlie these disorders are often classified as either a gain of toxic function or loss of normal protein function, some toxic mechanisms associated with mutant polyQ tracts will also be discussed.

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Huntington’s disease cerebrospinal fluid seeds aggregation of mutant huntingtin

Cited by 48 publications

References 42 publications

An image‐based model of brain volume biomarker changes in Huntington's disease

An image‐based model of brain volume biomarker changes in Huntington's disease

Formation and Structure of Wild Type Huntingtin Exon-1 Fibrils

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

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