SubsidieMeestersCellular Strategies of Protein Quality Control-Degradation
This project aims to uncover the molecular mechanisms of stress-induced protein quality control and E3 ubiquitin ligases to combat neurodegeneration from chronic protein damage.
Projectdetails
Introduction
Maintaining the quality of all proteins in an organism is fundamental to life since it ensures tissue function, organismal health, and longevity. Protein quality control (PQC) is achieved by selective degradation of damaged proteins, limiting the formation of protein aggregates and neurodegeneration characteristic of Alzheimer’s, Huntington’s, and Parkinson’s disorders.
Role of E3 Ubiquitin Ligases
Important regulators of cellular proteolysis are E3 ubiquitin ligases that target damaged proteins for degradation. However, therapeutically relevant E3 ligases specialized for PQC degradation (PQCD) are largely unknown. PQCD of damaged proteins is a dynamic process that must be coordinated with physiological and environmental challenges to overcome stress-induced proteotoxicity.
Challenges in the Field
Despite progress in characterizing regulatory signals for protein degradation, the major challenge in this field is to understand the dynamic rewiring of PQCD pathways under acute and chronic stress conditions.
Research Goals
Thus, the overall goal of the proposed research program is to unravel the molecular basis of stress-induced PQCD, which is critical for physiological integrity and health.
Methodology
The mechanistic role of PQC-E3 ubiquitin ligases will be investigated using mammalian cell cultures and the genetic model organism Caenorhabditis elegans, which reflects many conserved human ubiquitin-dependent PQCD pathways and allows for well-defined lifespan studies.
Innovative Approach
This innovative and interdisciplinary research program will combine state-of-the-art proteome analyses with tissue-specific manipulation of stress signals and large-scale genetic studies for identification and characterization of:
- Stress-induced PQCD
- Aggregating damaged proteins
- E3 ligases specialized for PQCD
Significance of the Research
Importantly, in addition to providing new molecular insights into stress-induced adaptive mechanisms, this research program will lay the foundation for exploring the pathophysiology of aggregation-related neurodegeneration triggered by chronic protein damage.
Financiële details & Tijdlijn
Financiële details
| Subsidiebedrag | € 2.500.000 |
| Totale projectbegroting | € 2.500.000 |
Tijdlijn
| Startdatum | 1-1-2025 |
| Einddatum | 31-12-2029 |
| Subsidiejaar | 2025 |
Partners & Locaties
Projectpartners
- UNIVERSITAT ZU KOLNpenvoerder
Land(en)
Vergelijkbare projecten binnen European Research Council
| Project | Regeling | Bedrag | Jaar | Actie |
|---|---|---|---|---|
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Mechanisms of human co-translational quality control and it’s role in neural tissue.This project aims to elucidate the mechanisms of ribosome-associated quality control in humans and its implications for neurodegeneration and aging, using cryo-EM and C. elegans models. | ERC Starting... | € 1.500.000 | 2024 | Details |
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The origin and impact of impaired ubiquitin signaling in the degeneration of neuronsThis project aims to investigate dysregulated ubiquitin signaling as an early cause of neurodegeneration, using innovative human neuronal models to enhance understanding and treatment of Alzheimer's disease. | ERC Advanced... | € 2.500.000 | 2024 | Details |
Understanding the molecular basis of protein folding disorders and protein quality control in muscle
This project aims to investigate muscle protein disorders in C. elegans by developing PQC tools to study myosin misfolding and identify cellular rescue mechanisms to enhance understanding of proteinopathies.
Mechanisms of human co-translational quality control and it’s role in neural tissue.
This project aims to elucidate the mechanisms of ribosome-associated quality control in humans and its implications for neurodegeneration and aging, using cryo-EM and C. elegans models.
Deciphering the regulatory logic of the ubiquitin system
This project aims to elucidate the substrate recognition mechanisms of E3 ubiquitin ligases using functional genetic approaches to enhance understanding of the ubiquitin-proteasome system for therapeutic applications.
Deciphering Cellular Networks for Membrane Protein Quality Control Decisions
This project aims to enhance understanding of membrane protein biogenesis and quality control in the endoplasmic reticulum, addressing key questions related to folding, chaperones, and disease mechanisms.
The origin and impact of impaired ubiquitin signaling in the degeneration of neurons
This project aims to investigate dysregulated ubiquitin signaling as an early cause of neurodegeneration, using innovative human neuronal models to enhance understanding and treatment of Alzheimer's disease.