Publications related to Huntington's disease

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

An integrative approach to elucidate the mechanisms and dynamics of Huntingtin aggregation and inclusion formation in neuronal models of Huntington's Disease

Nathan Alain Denis Riguet

Despite the fact that the gene responsible for Huntington's disease (HD) is known, we still do not understand the underlying mechanisms leading to neurodegeneration and death. Identifying and understanding the mechanisms controlling mutant huntingtin (mHtt ...

EPFL2022

Fading of brain network fingerprint in Parkinson's disease predicts motor clinical impairment

Enrico Amico, Antonella Romano

The clinical connectome fingerprint (CCF) was recently introduced as a way to assess brain dynamics. It is an approach able to recognize individuals, based on the brain network. It showed its applicability providing network features used to predict the cog ...

Wiley2023

Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing

Andrea Ablasser

Kessler et al. identify aberrant DNA recognition by cGAS/STING and IFN-I production by inflammatory macrophages as a driver of severe ANCA-associated vasculitis. Pharmacological interventions blocking this pathway ameliorate disease and accelerate recovery ...

ROCKEFELLER UNIV PRESS2022

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

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

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

Investigating Crosstalk Among PTMs Provides Novel Insight Into the Structural Basis Underlying the Differential Effects of Nt17 PTMs on Mutant Httex1 Aggregation

Hilal Lashuel, Matteo Dal Peraro, Luciano Andres Abriata, Lucien Fabrice Krapp, Anass Chiki, Driss Boudeffa, Iman Rostami, Rajasekhar Kolla, Zhidian Zhang

Post-translational modifications (PTMs) within the first 17 amino acids (Nt17) of the Huntingtin protein (Htt) have been shown to inhibit the aggregation and attenuate the toxicity of mutant Htt proteins in vitro and in various models of Huntington’s disea ...

2021

Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration

Hilal Lashuel, Sonia Donzelli

Alteration to endoplasmic reticulum (ER) proteostasis is observed in a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteost ...

2021

Rethinking protein aggregation and drug discovery in neurodegenerative diseases: Why we need to embrace complexity?

Hilal Lashuel

More than a century has passed since pathological protein aggregates were first identified in the brains of patients with neurodegenerative diseases (NDDs). Yet, we still do not have effective therapies to treat or slow the progression of these devastating ...

2021

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

Development of novel methods and tools to decipher the huntingtin post-translation modifications code

Anass Chiki

Huntington's disease (HD) is a fatal genetic neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin gene of more than 36 repeats. This repeat is translated into a polyglutamine (polyQ) stretch within the first exon-encoded region of ...

EPFL2020

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

TBK1 phosphorylates mutant Huntingtin and suppresses its aggregation and toxicity in Huntington's disease models

Johan Auwerx, Hilal Lashuel, Laurent Mouchiroud, Anass Chiki, Lara Petricca, Ramanath Narayana Hegde

Phosphorylation of the N‐terminal domain of the huntingtin (HTT ) protein has emerged as an important regulator of its localization, structure, aggregation, clearance and toxicity. However, validation of the effect of bona fide phosphorylation in vivo and ...

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

Site-Specific Phosphorylation of Huntingtin Exon 1 Recombinant Proteins Enabled by the Discovery of Novel Kinases

Hilal Lashuel, Luciano Andres Abriata, Jonathan Jean-Pierre Ricci, Anass Chiki, Andreas Reif, Ramanath Narayana Hegde, Driss Boudeffa

Post-translational modifications (PTMs) within the first 17 amino acids (Nt17) of exon 1 of the Huntingtin protein (Httex1) play important roles in modulating its cellular properties and functions in health and disease. In particular, phosphorylation of th ...

2020

Precision Targeting of pten-Null Triple-Negative Breast Tumors Guided by Electrophilic Metabolite Sensing

Yimon Aye, Xuyu Liu, Lingxi Wang, Chaosheng Luo

Off-target effects continue to impede disease interventions, particularly when targeting a specific protein within a family of similar proteins, such as kinase isoforms that play tumor-subtype-specific roles in cancers. Exploiting the specific electrophili ...

AMER CHEMICAL SOC2020

Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. "Alive, with good vision and no comorbidity"

Paul Joseph Dyson

Retinoblastoma is lethal by metastasis if left untreated, so the primary goal of therapy is to preserve life, with ocular survival, visual preservation and quality of life as secondary aims. Historically, enucleation was the first successful therapeutic ap ...

PERGAMON-ELSEVIER SCIENCE LTD2019

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