H2020Индивидуална стипендия2019–2022

NeuroFreezing · Biophysical Properties of the Neuronal Cytosol and their Dynamics upon Nutrient Starvation, Aging, and in Neurodegenerative Diseases.

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

Период: 2019-06-01 → 2022-08-11
Финансиране от ЕС: 203 149 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Невронната цитозолна течност се променя ли в твърдо състояние при недостиг на глюкоза или стареене, което да предизвика струпване на вредни протеини. Разбирането на този процес помага при търсенето на нови мишени за терапия срещу болестта на Хънтингтън и подобни заболявания.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Biophysical Properties of the Neuronal Cytosol and their Dynamics upon Nutrient Starvation, Aging, and in Neurodegenerative Diseases.

Neurodegenerative polyglutamine (polyQ) expansion disorders such as Huntington’s disease (HD) are devastating, progressive and ultimately fatal diseases with no effective treatment or cure. The molecular hallmark of the diseases is an age-dependent, neurotoxic aggregation of polyglutamine-proteins. The fundamental cellular processes triggering this neurotoxic protein aggregation are poorly understood, resulting in a scarcity of drug targets for developing therapeutic strategies. Interestingly, glucose uptake into the brain is reduced in both HD patients and animal models. Reduced brain glucose metabolism precedes both motor symptoms and tissue loss, and the degree of glucose-hypometabolism appears to affect age of symptom-onset, with larger decreases in glucose uptake correlating with earlier disease onset. Recent studies in yeast and bacteria in have shown that the material properties of the cytosol in these cells change upon reduced glucose-uptake, leading the liquid-like cytosol to appear more solid-like, which in turn results in increased protein aggregation. We hypothesized that a similar response to reduced glucose-metabolism may change the material properties of the neuronal cytosol and thereby contribute to triggering the neurotoxic aggregation of polyQ-proteins in HD and other neurodegenerative polyglutamine expansion disorders. The overall objectives of the project were to determine whether: 1. mammalian neurons regulate cytoplasmic diffusion and display a stress response that changes the material properties of the cytosol, and whether 2. this neuronal stress response upon nutrient-starvation or ageing is sufficient to trigger aggregation of polyglutamine-proteins.

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

Цел на проекта

The material properties of the cytosol control the biochemistry of the cell and influence all molecular interactions by regulating rates of intracellular diffusive transport. Despite this critical role, these properties remain poorly understood, and it is unclear to what extent the cytosol is homogeneous, whether there are differences between cell types, and if these properties are stable or dynamic. It has recently been discovered that yeast cells regulate their cytosolic properties in response to stress, namely glucose-starvation and aging. These stresses result in a decrease in cell volume and an increase in cytosolic crowding, inducing widespread phase separations and aggregation of polyglutamine (polyQ)-proteins. This type of polyQ-protein aggregation is the molecular hallmark of neurodegenerative diseases like Huntington's Disease (HD), and is very poorly understood. In this project, I will produce the first description of the biophysical properties of the neuronal cytosol, and I will directly test whether aged or nutrient-deprived neurons, or neurons from an HD mouse model exhibit changes in these properties. I propose that viscosity and density of mammalian cells, and in particular neuronal cells, are dynamic properties that can be actively regulated in response to environmental changes. In particular, I will test two hypotheses: - H1: Nutrient starvation and aging induce changes to the material properties of the neuronal cytosol. - H2: A neuronal stress-response upon starvation or aging is sufficient to trigger aggregation of polyQ-proteins. Combining state-of-the-art techniques and expertise in the fields of neurobiology, metabolism, and biophysics, my investigation of these novel and potentially paradigm shifting hypotheses could fundamentally alter our understanding of the material properties of the neuronal cytosol, and ultimately reveal new therapeutic strategies for the most common inherited neurodegenerative disorders.

Оригинален текст от CORDIS (на английски).

Участници

EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH · ZuerichКоординаторШвейцария