UnfearHD
Financiado
Unfolding the early Htt aggregates: an interdisciplinary approach for characteri...
Unfolding the early Htt aggregates: an interdisciplinary approach for characterizing novel molecular events that impact Heat Shock Response in Huntington Disease
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 a...
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.
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Duración del proyecto: 24 meses
Fecha Inicio: 2023-05-04
Fecha Fin: 2025-05-31
Fecha Fin: 2025-05-31
Línea de financiación: concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-05-04
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
Presupuesto
El presupuesto total del proyecto asciende a
169K€
Líder del proyecto
IDRYMA TECHNOLOGIAS KAI EREVNAS
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5