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Ubiquitin Signaling as a Key Regulator of Aging and Neurodegeneration

Obiettivo

Loss of protein homeostasis (proteostasis) is a critical feature of aging and a major driver of neurodegenerative diseases such as Huntington’s and ALS. A key guardian of proteome integrity is ubiquitination, a versatile post-translational modification that controls protein degradation, localization, and activity. Remarkably, disease-associated protein aggregates are ubiquitin-positive, yet how age-related remodeling of ubiquitination disrupts proteostasis and accelerates functional decline remains unknown. My recent work revealed that aging causes a global remodeling of the ubiquitin landscape. Particularly, age-dependent alterations in ubiquitin-mediated proteasomal degradation determine both lifespan and neurodegeneration in C. elegans. These findings uncover ubiquitination as a molecular determinant of aging, but the underlying mechanisms and systemic consequences are unexplored. This project will establish the comprehensive framework for ubiquitination in aging and neurodegeneration. We will (1) define how altered ubiquitination impacts autophagy and protein aggregation, (2) unravel the intracellular and inter-tissue mechanisms that regulate ubiquitin signaling across lifespan, and (3) dissect how ubiquitination coordinates crosstalk among distinct aging hallmarks, including genomic instability and proteostasis, using premature aging syndromes as a paradigm. By combining state-of-the-art proteomics, C. elegans genetics, and patient-derived iPSC models, this research will uncover fundamental principles by which ubiquitin signaling shapes proteome integrity, organismal homeostasis, and longevity. Additionally, this project will open new avenues for therapeutic intervention against aging and neurodegenerative diseases.

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HORIZON-ERC - HORIZON ERC Grants

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(si apre in una nuova finestra) ERC-2026-STG

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Istituzione ospitante

JOHANN WOLFGANG GOETHE-UNIVERSITAET FRANKFURT AM MAIN
Contributo netto dell'UE
€ 1 489 985,00
Indirizzo
THEODOR W ADORNO PLATZ 1
60323 Frankfurt Am Main
Germania
Regione
Hessen Darmstadt Frankfurt am Main, Kreisfreie Stadt
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 1 489 985,00

Beneficiari (1)