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Concept

Spinocerebellar ataxia

Related publications (27)

Closed-Loop Control of Epidural Electrical Stimulation in Patients with Spinal Cord Injury and Parkinson's Disease

Nicolò Macellari

Over the past two decades, epidural electrical stimulation (EES) has transitioned from a treatment for chronic pain to a promising paradigm for ameliorating deficits associated with neurological disorders like spinal cord injury (SCI) and Parkinson's Disea ...

EPFL2023

Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates

Hilal Lashuel, Anass Chiki

Huntington's disease (HD) is caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene coding for the huntingtin (HTT) protein. The misfolding and consequential aggregation of CAG-expanded mutant HTT (mHTT) underpin HD p ...

Nature Portfolio2021

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, Rajasekhar Kolla, Jonathan Jean-Pierre Ricci, Andreas Reif, 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

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

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, Maria Josefina Marcaida Lopez, Giorgio Elikem Tamo

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

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

Marion Leleu, Flavia Marzetta, Ludovica Vanzan

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

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

Hilal Lashuel, Anass Chiki, 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

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

Hilal Lashuel, 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

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

Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity

Matteo Dal Peraro, Deniz Aydin

The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesi ...

Cell Press2016

Nanoscale studies link amyloid maturity with polyglutamine diseases onset

Hilal Lashuel, Giovanni Dietler, 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

One-Pot Semisynthesis of Exon 1 of the Huntingtin Protein: New Tools for Elucidating the Role of Posttranslational Modifications in the Pathogenesis of Huntington's Disease

Giovanni Dietler, Hilal Lashuel, Francesco Simone Ruggeri, Annalisa Ansaloni, Jae Sun Jeong

The natural enzymes involved in regulating many of the posttranslational modifications (PTMs) within the first 17 residues (Nt17) of Huntingtin exon1 (Httex1) remain unknown. A semisynthetic strategy that allows the site-specific introduction of PTMs withi ...

Wiley-Blackwell2014

Exploring new therapeutic strategies for Huntington's Disease

Wanqiu Hu

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an extended poly-glutamine tract in the huntingtin gene (HTT). Despite intensive efforts in understanding its pathogenesis over the decades, effective treatments for HD remain u ...

EPFL2014

MUNDUS project: MUltimodal Neuroprosthesis for daily Upper limb Support

Silvestro Micera, Andrea Crema

Background: MUNDUS is an assistive framework for recovering direct interaction capability of severely motor impaired people based on arm reaching and hand functions. It aims at achieving personalization, modularity and maximization of the user's direct inv ...

BioMed Central2013

A Hydrophobic Gold Surface Triggers Misfolding and Aggregation of the Amyloidogenic Josephin Domain in Monomeric Form, While Leaving the Oligomers Unaffected

Alessandra Apicella

Protein misfolding and aggregation in intracellular and extracellular spaces is regarded as a main marker of the presence of degenerative disorders such as amyloidoses. To elucidate the mechanisms of protein misfolding, the interaction of proteins with ino ...

Public Library Science2013

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

Gene expression profiling of R6/2 transgenic mice with different CAG repeat lengths reveals genes associated with disease onset and progression in Huntington's disease

R6/2 transgenic mice with expanded CAG repeats (> 300) have a surprisingly prolonged disease progression and longer lifespan than prototypical parent R6/2 mice (carrying 150 CAGs); however, the mechanism of this phenotype amelioration is unknown. We compar ...

Elsevier2011

Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model

Hilal Lashuel

α-Synuclein aggregates in Lewy bodies and plays a central role in the pathogenesis of a group of neurodegenerative disorders, known as "Synucleinopathies", including Parkinson's disease. Parkin mutations result in loss of parkin E3-ubiquitin ligase activit ...

2010

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