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HEIndividual fellowship2023–2025

Tau DG RT-imaging · Real-time imaging and mechanistic analysis of Tau fibril disaggregation in live cells

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-09-01 → 2025-08-31
EU contribution
€173,847
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

Lines connect the coordinator with its partners.

Results in brief

Real-time imaging and mechanistic analysis of Tau fibril disaggregation in live cells

Alzheimer’s disease and related brain disorders are among the most important medical challenges of our time. As people live longer, the number of patients continues to increase, placing enormous pressure on families, healthcare systems, and society. Current treatments provide only limited benefits, and new approaches are urgently needed. One of the hallmarks of Alzheimer’s disease is the abnormal deposition of the protein Tau. Normally, Tau acts like the trees of a healthy forest, giving stability and structure to nerve cells. But under disease conditions, Tau changes its structure and becomes unstable. Like dry tinder ready to catch fire, misfolded Tau molecules act as sparks that ignite nearby healthy “trees” and ignite new fires. These sparks represent toxic protein clumps (so-called aggregates) that trigger a chain reaction, leading to the larger ‘fires’ of aggregation spreading from cell to cell. The build-up and multiplication of these toxic aggregates over time is thought to be one of the main drivers of dementia. Past therapies mainly focused on removing the large “fires” or plaques in the brain. The results were modest and sometimes harmful, showing that tackling only the big flames is not enough. This project set out to understand how the first sparks appear in the form of small aggregates termed oligomers, how they spread through the forest, and how the brain’s natural “firefighters”, so-called molecular chaperones, try to put them out. By using advanced microscopy in living cells, we aimed to create a new framework for understanding Alzheimer’s disease and to pave the way for safer and more effective therapies.

Data: CORDIS, © European Union

Project objective

Age-dependent neurodegenerative diseases associated with protein aggregation represent one of the most important medical and socio-economic challenges of our time. With the extension of human life span, the prevalence of this group of diseases has markedly increased. Among them, Alzheimer’s diseases (AD) and other dementias have become the second leading cause of death in high-income countries. As a pathological hallmark, Tau amyloid aggregation in the brain has been determined to be closely related to the cognitive impairment in AD and related dementias. Despite major research efforts world-wide, the mechanism of Tau pathology and how its manifestation is prevented in healthy cells is not yet understood.This project builds on recent findings in the host laboratory that the AAA+ ATPase complex of VCP can mediate the disaggregation of Tau fibrils in a cellular model. Consistently, autosomal dominant VCP hypomorph mutations have been found to exacerbate Tau pathology in patients. I will use live cell fluorescence imaging and advanced single-molecule tracking to investigate the mechanism of VCP and cooperating factors in Tau disaggregation in real time. Stable reporter cell lines will be generated in which components of interest carry self-labeling affinity tags to introduce fluorescence signals for single-molecule monitoring. The planned research will provide new insights into the cellular pathways of fibril decomposition and may benefit the development of new therapeutic strategies for tauopathies. The experimental approach to be established in this study can be applied to investigate disaggregation in other neurodegenerative disorders, including Huntington’s and Parkinson’s disease.

Original text from CORDIS.

Participants

  • MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV · MUNCHENCoordinatorGermany

Links

Data: CORDIS, © European Union