Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

Trepte, Philipp; Strempel, Nadine U.; Wanker, Erich E.

doi:10.1042/bse0560167

Cited by 13 publications

(9 citation statements)

References 50 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4A, HC82 to H_0878, MW8). Given that the exon 1 HTT protein aggregates rapidly 27, 28 , we wondered whether the lack of a monomeric exon 1 HTT signal in the post-mortem brains was due to the fact that the exon 1 HTT protein had aggregated. Therefore, we immunoprecipitated HTT and HTT fragments at different stages of disease from the brains of zQ175 knock-in HD mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients

Neueder

Landles

Ghosh

et al. 2017

Sci Rep

185

142

View full text Add to dashboard Cite

We have previously shown that exon 1 of the huntingtin gene does not always splice to exon 2 resulting in the production of a small polyadenylated mRNA (HTTexon1) that encodes the highly pathogenic exon 1 HTT protein. The level of this read-through product is proportional to CAG repeat length and is present in all knock-in mouse models of Huntington’s disease (HD) with CAG lengths of 50 and above and in the YAC128 and BACHD mouse models, both of which express a copy of the human HTT gene. We have now developed specific protocols for the quantitative analysis of the transcript levels of HTTexon1 in human tissue and applied these to a series of fibroblast lines and post-mortem brain samples from individuals with either adult-onset or juvenile-onset HD. We found that the HTTexon1 mRNA is present in fibroblasts from juvenile HD patients and can also be readily detected in the sensory motor cortex, hippocampus and cerebellum of post-mortem brains from HD individuals, particularly in those with early onset disease. This finding will have important implications for strategies to lower mutant HTT levels in patients and the design of future therapeutics.

show abstract

Section: Resultsmentioning

confidence: 99%

The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients

Neueder

Landles

Ghosh

et al. 2017

Sci Rep

185

142

View full text Add to dashboard Cite

show abstract

“…Dysregulation of this interaction network by the polyQ expansion and subsequent aggregation is thought to be responsible for the resultant phenotype [29,30] , sometimes described as a gain-of-function. Most published work to date on HTT oligomers and their associated neuropathology has focussed on the so-called exon 1 proteins [31,32] . HTT is cleaved by a variety of caspases, calpains and endopeptidases to yield a variety of N-terminal fragments, including a short sequence encoding exon 1 of the protein, corresponding to the first 90 amino acids of HTT [31,32] .…”

Section: Acta Pharmacologica Sinicamentioning

confidence: 99%

“…Most published work to date on HTT oligomers and their associated neuropathology has focussed on the so-called exon 1 proteins [31,32] . HTT is cleaved by a variety of caspases, calpains and endopeptidases to yield a variety of N-terminal fragments, including a short sequence encoding exon 1 of the protein, corresponding to the first 90 amino acids of HTT [31,32] . Exon 1 is comprised of the N-terminal 17 amino acids (N17), the polyQ tract and then a 51-residue proline-rich domain (PRD).…”

Section: Acta Pharmacologica Sinicamentioning

confidence: 99%

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities

Harding

Tong

2018

Acta Pharmacol Sin

View full text Add to dashboard Cite

Many neurodegenerative diseases are characterized by impairment of protein quality control mechanisms in neuronal cells. Ineffective clearance of misfolded proteins by the proteasome, autophagy pathways and exocytosis leads to accumulation of toxic protein oligomers and aggregates in neurons. Toxic protein species affect various cellular functions resulting in the development of a spectrum of different neurodegenerative proteinopathies, including Huntington's disease (HD). Playing an integral role in proteostasis, dysfunction of the ubiquitylation system in HD is progressive and multi-faceted with numerous biochemical pathways affected, in particular, the ubiquitin-proteasome system and autophagy routes for protein aggregate degradation. Unravelling the molecular mechanisms involved in HD pathogenesis of proteostasis provides new insight in disease progression in HD as well as possible therapeutic avenues. Recent developments of potential therapeutics are discussed in this review.

show abstract

“…HTT is a large protein of ~ 350 kDa that plays critical functional roles in gene expression regulation (Valor ), vesicle transport (Harjes and Wanker ) and autophagy (Ochaba et al ). It is modified post‐translationally at multiple sites (Cariulo et al ; Harding et al ) and gets cleaved by various proteases (Sanchez Mejia and Friedlander ), leading to the release of N‐terminal fragments with an expanded polyQ sequence, which have a high propensity to misfold and self‐assemble into fibrillar aggregates (Scherzinger et al ; Trepte et al ). As a consequence, intranuclear inclusions are formed in neurons.…”

Section: Abnormal Interactions Are Commonly Found In Genetic Diseasesmentioning

confidence: 99%

The pathobiology of perturbed mutant huntingtin protein–protein interactions in Huntington's disease

Wanker

Ast

Schindler

et al. 2019

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

Mutations are at the root of many human diseases. Still, we largely do not exactly understand how they trigger pathogenesis. One, more recent, hypothesis has been that they comprehensively perturb protein-protein interaction (PPI) networks and significantly alter key biological processes. Under this premise, many rare genetic disorders with Mendelian inheritance, like Huntington's disease and several spinocerebellar ataxias, are likely to be caused by complex genotype-phenotype relationships involving abnormal PPIs. These altered PPI networks and their effects on cellular pathways are poorly understood at the molecular level. In this review, we focus on PPIs that are perturbed by the expanded pathogenic polyglutamine tract in huntingtin (HTT), the protein which, in its mutated form, leads to the autosomal dominant, neurodegenerative Huntington's disease. One aspect of perturbed mutant HTT interactions is the formation of abnormal protein species such as fibrils or large neuronal inclusions as a result of homotypic and heterotypic aberrant molecular interactions. This review focuses on abnormal PPIs that are associated with the assembly of mutant HTT aggregates in cells and their potential relevance in disease. Furthermore, the mechanisms and pathobiological processes that may contribute to phenotype development, neuronal dysfunction and toxicity in Huntington's disease brains are also discussed.

show abstract

Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

Cited by 13 publications

References 50 publications

The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients

The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities

The pathobiology of perturbed mutant huntingtin protein–protein interactions in Huntington's disease

Contact Info

Product

Resources

About