Unfolding the early Htt aggregates: an interdisciplinary approach for characterizing novel molecular events that impact Heat Shock Response in Huntington Disease

Información del proyecto

UnfearHD

Identificador del acuerdo de subvención: 101130833

DOI

10.3030/101130833

Proyecto cerrado

Fecha de la firma de la CE 4 Mayo 2023

Fecha de inicio 1 Junio 2023

Fecha de finalización 31 Mayo 2025

Financiado con arreglo a

• Widening participation and spreading excellence

Coste total

Sin datos

Aportación de la UE

€ 169 326,72

Coordinado por

IDRYMA TECHNOLOGIAS KAI EREVNAS
Greece

Objetivo

A common characteristic in many neurodegenerative diseases (NDs) is the presence of disordered proteins that form toxic aggregates. In Huntington’s disease (HD), expanded polyQ tracts on Huntingtin (Htt) lead to the formation of aggregates, which affects many cellular functions, eventually resulting in cell death. Heat Shock Response (HSR) is a protective mechanism that facilitates (among other functions) the clearance of protein aggregates. Paradoxically, HSR becomes impaired in HD. The fact that early Htt aggregates, prior to becoming severely aggregated or toxic, fail to trigger HSR indicates that this impairment likely occurs early in the HD pathogenesis. The molecular mechanism underlining the HSR impairment in HD remains elusive. The aim of UnFearHD is to unravel the mechanism that links Htt aggregation with HSR impairment in early stages of HD.
Several lines of evidence indicate that disordered proteins, having the ability to phase separate, may directly regulate translation and transcription, as shown for biomolecular condensates. Our hypothesis is that aggregation-prone Htt alters the early HD proteome composition in a way that impacts the HSR, by directly interacting with RNA and DNA. To explore our hypothesis, we will employ C. elegans strains engineered for inducible Htt expression and combine unbiased omics to a) directly interrogate the Htt interactions with RNAs and DNAs, using a UV-based crosslinking and immunoprecipitation (CLIP) and b) understand the consequences of such interactions at proteome level, using a bioorthogonal non-canonical amino acid tagging (BONCAT). The UnfearHD project will enable the establishment, for the first time, of a direct association between Htt aggregation and HSR impairment, which is detrimental for HD progression. The findings will stretch beyond the scope of UnfearHD as the combination of protein aggregation and HSR impairment is detrimental for other NDs but also seems to constitutes a universal mechanism of ageing.

Ámbito científico (EuroSciVoc)

• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas › proteómica
• ciencias naturales › ciencias biológicas › genética › ADN
• ciencias naturales › ciencias biológicas › genética › ARN

Palabras clave

• C. elegans
• Huntingtin
• Chemical Biology
• protein aggregation

Programa(s)

• HORIZON.4.1 - Widening participation and spreading excellence PROGRAMA PRINCIPAL
  
• HORIZON.4.1.5 - Fostering brain circulation of researchers and excellence initiatives
  

Tema(s)

• HORIZON-WIDERA-2022-TALENTS-04-01 - Fostering balanced brain circulation – ERA Fellowships
  

Régimen de financiación

HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

Convocatoria de propuestas

HORIZON-WIDERA-2022-TALENTS-04

Coordinador

IDRYMA TECHNOLOGIAS KAI EREVNAS

• Aportación neta de la UEn: € 169 326,72
• Dirección: N PLASTIRA STR 100 ; 70 013 IRAKLEIO ; Grecia
• Región: Νησιά Αιγαίου › Κρήτη › Ηράκλειο
• Tipo de actividad: Research Organisations
• Coste total: Sin datos