Publications related to Polyglutamine tract

N-terminal mutant huntingtin deposition correlates with CAG repeat length and symptom onset, but not neuronal loss in Huntington's disease

Hilal Lashuel, Lorène Aeschbach, Nathan Alain Denis Riguet

Huntington's disease (HD) is caused by a CAG repeat expansion mutation in the gene encoding the huntingtin (Htt) protein, with mutant Htt protein subsequently forming aggregates within the brain. Mutant Htt is a current target for novel therapeutic strateg ...

ACADEMIC PRESS INC ELSEVIER SCIENCE2022

A New Chemoenzymatic Semisynthetic Approach Provides Insight into the Role of Phosphorylation beyond Exon1 of Huntingtin and Reveals N-Terminal Fragment Length-Dependent Distinct Mechanisms of Aggregation

Hilal Lashuel, Jonathan Jean-Pierre Ricci, Andreas Reif, Rajasekhar Kolla, Iman Rostami, Gopinath Pushparathinam

Huntington’s disease is a neurodegenerative dis- order caused by the expansion of a polyglutamine repeat (>36Q) in the N-terminal domain of the huntingtin protein (Htt), which renders the protein or fragments thereof more prone to aggregate and form inclus ...

2021

The Nt17 Domain and its Helical Conformation Regulate the Aggregation, Cellular Properties and Neurotoxicity of Mutant Huntingtin Exon 1

Giovanni Dietler, Hilal Lashuel, Anne-Laure Mahul Mellier, Francesco Simone Ruggeri, Anass Chiki, Sean Michael Deguire, Urszula Beata Cendrowska, Sophie Vieweg, Nathan Alain Denis Riguet

Converging evidence points to the N-terminal domain comprising the first 17 amino acids of the Huntingtin protein (Nt17) as a key regulator of its aggregation, cellular properties and toxicity. In this study, we further investigated the interplay between N ...

Elsevier2021

The Polyglutamine Expansion at the N-Terminal of Huntingtin Protein Modulates the Dynamic Configuration and Phosphorylation of the C-Terminal HEAT Domain

Matteo Dal Peraro, Giorgio Elikem Tamo, Maria Josefina Marcaida Lopez, Ruedi Aebersold

The polyQ expansion in huntingtin protein (HTT) is the prime cause of Huntington's disease (HD). The recent cryoelectron microscopy (cryo-EM) structure of HTT-HAP40 complex provided the structural information on its HEAT-repeat domains. Here, we present an ...

CELL PRESS2020

Ultrasensitive quantitative measurement of huntingtin phosphorylation at residue S13

Hilal Lashuel, Lara Petricca, Sean Michael Deguire

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of a CAG triplet repeat (encoding for a polyglutamine tract) within the first exon of the huntingtin gene. Expression of the mutant huntingtin (mHTT) protein can r ...

ACADEMIC PRESS INC ELSEVIER SCIENCE2020

Nicotinamide Pathway-Dependent Sirt1 Activation Restores Calcium Homeostasis to Achieve Neuroprotection in Spinocerebellar Ataxia Type 7

Johan Auwerx, Karim Laurent Gariani

Sirtuin 1 (Sirt1) is a NAD(+)-dependent deacetylase capable of countering age-related neurodegeneration, but the basis of Sirt1 neuroprotection remains elusive. Spinocerebellar ataxia type 7 (SCA7) is an inherited CAG-polyglutamine repeat disorder. Transcr ...

2020

Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion

Marion Leleu, Ludovica Vanzan, Flavia Marzetta, Ioannis Xenarios

Expanded CAG/CTG repeats underlie 13 neurological disorders, including myotonic dystrophy type 1 (DM1) and Huntington's disease (HD). Upon expansion, disease loci acquire heterochromatic characteristics, which may provoke changes to chromatin conformation ...

2020

Generation of Native, Untagged Huntingtin Exon1 Monomer and Fibrils Using a SUMO Fusion Strategy

Hilal Lashuel, Jonathan Jean-Pierre Ricci, Anass Chiki, Andreas Reif

Huntington’s Disease (HD) is an inherited fatal neurodegenerative disease caused by a CAG expansion (36) in the first exon of the HD gene, resulting in the expression of the Huntingtin protein (Htt) or N-terminal fragments thereof with an expanded polygl ...

2018

Polyglutamine expansion affects huntingtin conformation in multiple Huntington’s disease models

Hilal Lashuel, Lara Petricca, Sean Michael Deguire

Conformational changes in disease-associated or mutant proteins represent a key pathological aspect of Huntington's disease (HD) and other protein misfolding diseases. Using immunoassays and biophysical approaches, we and others have recently reported that ...

Springer Nature2017

Phosphorylation of huntingtin at residue T3 is decreased in Huntington’s disease and modulates mutant huntingtin protein conformation

Hilal Lashuel, Anass Chiki, Lara Petricca, Sean Michael Deguire

Posttranslational modifications can have profound effects on the biological and biophysical properties of proteins associated with misfolding and aggregation. However, their detection and quantification in clinical samples and an understanding of the mecha ...

2017

The role of the polyglutamine and N-terminal domains in regulating the aggregation and structural properties of Huntingtin Exon 1

Sophie Vieweg

Huntington Disease (HD) is caused by a CAG repeat expansion in the huntingtin gene leading to the formation of mutant Huntingtin protein (Htt) with an expanded polyglutamine (polyQ) domain (>36Q). Generation of short N-terminal Htt fragments by proteolysis ...

EPFL2017

Monomeric Huntingtin Exon 1 Has Similar Overall Structural Features for Wild-Type and Pathological Polyglutamine Lengths

Hilal Lashuel, John Blaine Warner IV

Huntington’s disease is caused by expansion of a polyglutamine (polyQ) domain within exon 1 of the huntingtin gene (Httex1). A popular hypothesis is that the Httex1 protein undergoes sharp conformational changes as the polyQ length exceeds a threshold of 3 ...

2017

Nanoscale studies link amyloid maturity with polyglutamine diseases onset

Giovanni Dietler, Hilal Lashuel, Giovanni Longo, Francesco Simone Ruggeri, Urszula Beata Cendrowska

The presence of expanded poly-glutamine (polyQ) repeats in proteins is directly linked to the pathogenesis of several neurodegenerative diseases, including Huntington's disease. However, the molecular and structural basis underlying the increased toxicity ...

Nature Research2016

Cytoplasmic Ubiquitin-Specific Protease 19 (USP19) Modulates Aggregation of Polyglutamine-Expanded Ataxin-3 and Huntingtin through the HSP90 Chaperone

Françoise Gisou van der Goot Grunberg

Ubiquitin-specific protease 19 (USP19) is one of the deubiquitinating enzymes (DUBs) involved in regulating the ubiquitination status of substrate proteins. There are two major isoforms of USP19 with distinct C-termini; the USP19_a isoform has a transmembr ...

Public Library of Science2016

An Intein-based Strategy for the Production of Tag-free Huntingtin Exon 1 Proteins Enables New Insights into the Polyglutamine Dependence of Httex1 Aggregation and Fibril Formation

Hilal Lashuel, Annalisa Ansaloni, Sophie Vieweg, John Blaine Warner IV

The first exon of the Huntingtin protein (Httex1) is one of the most actively studied Htt fragments because its overexpression in R6/2 transgenic mice has been shown to recapitulate several key features of Huntington disease. However, the majority of bioph ...

Amer Soc Biochemistry Molecular Biology Inc2016

Gene expression analysis on a single cell level in Purkinje cells of Huntington's disease transgenic mice

Ataxia is a clinical feature of most polyglutamine disorders. Cerebellar neurodegeneration of Purkinje cells (PCs) in Huntington's Disease (HD) brain was described in the 1980s. PC death in the R6/2 transgenic model for HD was published by Turmaine et al. ...

2012

Comparative analyses of Purkinje cell gene expression profiles reveal shared molecular abnormalities in models of different polyglutamine diseases

Polyglutamine (PolyQ) diseases have common features that include progressive selective neurodegeneration and the formation of protein aggregates. There is growing evidence to suggest that critical nuclear events lead to transcriptional alterations in PolyQ ...

Elsevier Science Bv2012

Sustained Effects of Nonallele-Specific Huntingtin Silencing

Nicole Déglon

Objective: Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin (htt) protein. No cure is available to date to alleviate neurodegeneration. Recent studies have demonstrated ...

Wiley-Blackwell2009

Implication of the JNK pathway in a rat model of Huntington's disease

Patrick Aebischer, Nicole Déglon

Huntington's disease (HD) is a neurodegenerative disorder resulting from the expansion of a glutamine repeat (polyQ) in the N-terminus of the huntingtin (htt) protein. Expression of polyQ-containing proteins has been previously shown to induce various cell ...

2009

Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease

Nicole Déglon

Machado-Joseph disease (MJD) is a fatal, dominant neurodegenerative disorder. MJD results from polyglutamine repeat expansion in the MJD-1 gene, conferring a toxic gain of function to the ataxin-3 protein. In this study, we aimed at overexpressing ataxin-3 ...

Oxford University Press2008