Secretion, Autophagy and their role in Neurodegeneration

Project Information

SAND

Grant agreement ID: 860035

DOI

10.3030/860035

Project closed

EC signature date 2 September 2019

Start date 1 November 2019

End date 31 October 2024

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 4 076 578,42

EU contribution

€ 4 076 578,42

Coordinated by

UNIVERSITETET I OSLO
Norway

Periodic Reporting for period 2 - SAND (Secretion, Autophagy and their role in Neurodegeneration)

Reporting period: 2021-11-01 to 2024-10-31

Summary of the context and overall objectives of the project

Neurodegenerative disorders (NDs), such as Huntington's disease (HD), Parkinson's disease (PD), and Alzheimer's disease (AD), pose significant health challenges in our aging society and are among the leading causes of death. These disorders often involve the accumulation of toxic protein aggregates, like amyloid plaques and Lewy bodies, and subsequent neuronal death in specific parts of the central nervous system. These aggregates can arise from familial or sporadic genetic mutations in the proteins themselves or from disruptions in cellular proteostasis, which is the balance of protein production, sorting, and turnover. The secretory and autophagic pathways are crucial regulators of proteostasis, and their dysfunction can lead to NDs. The SAND project aimed to deepen our understanding of these pathways and their roles in NDs. The specific objectives included: 1) uncovering the fundamental mechanisms of the autophagy and secretory pathways and their interactions; 2) clarifying how these pathways contribute to NDs; and 3) identifying new drug targets and diagnostic markers for tackling NDs. Through their work on various SAND projects, a new generation of early-stage researchers (ESRs) has been trained in essential scientific and transferable skills for future careers in academia or industry.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The projects of SAND have focused on three main research areas: 1) Fundamental, 2) Neuro, and 3) Drugs and Biomarkers, fostering collaboration between groups to translate fundamental discoveries into clinical neuroscience. In the Fundamental area, five ESRs have investigated the basic mechanisms of secretory trafficking and autophagy and how they relate to protein aggregation and stress granule formation, and their impacts on neurodegeneration. In the Neuro area, seven ESRs have used cellular and animal models, such as Drosophila, zebrafish, and mice, to explore the effects of changes in protein secretion and autophagy crosstalk on neurodegeneration in conditions like ALS, PD, and AD. The Drugs and Biomarkers area involved three ESRs employing various approaches to assess potential regulators of the autophagy-secretion crosstalk that may function as therapeutic targets or biomarkers for NDs. All ESRs have gained core scientific skills through their research projects, annual meetings, lab exchanges, and participation in workshops and conferences.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The SAND project has achieved advancements beyond current knowledge, as evidenced by presentations at our four annual meetings (2020-2023) and at various national and international scientific conferences, as well as more than 25 scientific publications in international peer-reviewed journals to date. These achievements include discovering new factors involved in autophagy and secretion regulation, understanding the mechanisms of protein aggregate formation, identifying interaction partners and post-translational changes in aggregate-prone proteins, developing new cell and animal models to study NDs, and characterizing chemical compounds that influence autophagy and secretion. In conclusion, the results obtained within SAND provide a deeper insight into the mechanisms of autophagy, secretion, their interaction, and their roles in protein aggregation and ND development.

By integrating expertise from diverse fields, including vesicular trafficking, autophagy, chemical biology, neuroscience, computational sciences, systems biology, and clinical neurology, SAND has bridged basic research to translational applications, paving the way for potential new treatments for NDs. This is vital, as NDs are projected to become the second leading cause of death in the next 20 years, with an aging population. Thus, SAND's outcomes hold significant interest for both the research community and the clinical and industrial sectors. Moreover, through an extensive training program, SAND ESRs have obtained highly valuable skills necessary for successful careers in academia or the industry.

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