H2020Индивидуална стипендия2017–2019

REVERSING TAUOPATHY · Identifying and deciphering the mechanism of the cellular machinery responsible for disaggregation of intracellular prion-like Tau aggregates

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2017-06-01 → 2019-05-31
Финансиране от ЕС: 171 461 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Механизмите, чрез които клетките разграждат вредните протеинови натрупвания (като при болестта Алцхаймер), са в центъра на анализа. Разбирането на този процес помага за разработването на нови терапевтични стратегии за почистване на токсичните агрегати в мозъка.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Identifying and deciphering the mechanism of the cellular machinery responsible for disaggregation of intracellular prion-like Tau aggregates

Protein aggregation is a phenomenon which results due to inadequacy of the cellular machinery to deal with misfolded or non-native proteins. It has been found to be associated with a number of human pathological disorders including neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and Prion diseases. Aggregation of the neuronal protein Tau results in the formation of fibrillar, rod-like structures (known as amyloid fibrils) in the brain, a phenomenon that has been implicated in a number of neurodegenerative diseases (tauopathies), including Alzheimer’s disease, frontotemporal dementia, progressive supranuclear palsy, Pick disease, primary age related tauopathy, and corticobasal degeneration. According to the World Health Organization, more than 47 million people worldwide are affected by dementia, with Alzheimer’s disease being the most common and widespread among them (60-70%). In this study, we were able to identify the conditions wherein intracellular Tau aggregates were found to be disassembled or disaggregated. Moreover, we were able to pinpoint the cellular machinery responsible for the disaggregation process. This study provides an opportunity to design therapeutic strategies for neurodegeneration affecting the disaggregation machinery for improved aggregate clearance. Inside cells, protein misfolding is an unfavorable event that can result in the loss of biological activity or the formation of soluble and insoluble aggregates, the latter being associated with toxic effects underlying a number of human pathological disorders. Cells have mechanisms in place to prevent these aggregates from forming, either by preventing protein misfolding with molecular chaperones or by degrading misfolded proteins via proteolytic machineries. However, cellular machinery very frequently cannot take care of misfolded proteins, leading to their aggregation and accumulation in cells and tissues. Such protein aggregation has been implicated in a number of human pathological disorders including neurodegenerative diseases. Aggregation of the protein Tau has been implicated in Alzheimer’s disease, frontotemporal dementia and other pathologies referred to as tauopathies. Despite major research efforts world-wide, the mechanism of Tau aggregation and its pathogenesis giving rise to disease is not yet understood. Therapeutics to cure these tauopathies, including Alzheimer’s disease, are urgently needed. In our study, we were able to identify the conditions wherein intracellular Tau aggregates were found to be disassembled or disaggregated. Moreover, we were able to pinpoint the cellular machinery responsible for the disaggregation process.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Tauopathies are a group of neurodegenerative diseases, the most common of them being Alzheimer’s disease, which are associated with the aggregation of protein Tau in the brain. Despite major research efforts world-wide, the mechanism of Tau aggregation and its pathogenesis giving rise to such neurodegenerative diseases is not yet understood. Therapeutics to cure these tauopathies, including Alzheimer’s disease, are urgently needed. We aim to identify the conditions, the cellular machinery responsible and the mechanism of disaggregation of intracellular prion-like Tau aggregates in HEK293 cell lines, with one condition already been identified (starvation). For identifying the conditions of disaggregation, high resolution confocal microscopy will be used for visualizing intracellular Tau aggregates tagged with yellow fluorescence protein (YFP). For deciphering the cellular components responsible for disaggregation, the proteins associated with the aggregates will be identified using quantitative mass spectrometry from SILAC (stable isotope labeling with amino acids in cell culture) labeled cells. Moreover, candidate factors will be downregulated by siRNA to establish their involvement in aggregate disassembly. Such components individually and in combination will then be analyzed for their disaggregation activity in vitro using filter trap assay for the quantification of disaggregation. Cryo-electron tomography of Tau aggregates under various conditions (e.g. during disaggregation) will be carried out in collaboration with Prof. Wolfgang Baumeister (MPIB). Besides contributing to the benefit of humankind, the proposed research work on neurodegenerative diseases will allow me to grow as a researcher and will help me in realizing my true potential as a scientist. The MPIB and the Hartl lab in particular will play an important role in this regard due the availability of state-of-the-art research facilities and an intellectually stimulating environment.

Оригинален текст от CORDIS (на английски).

Участници

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV · MUNCHENКоординаторГермания