MEREMY6 · Uncovering the mechanism and physiological relevance of myosin-VI-dependent AMPA receptor trafficking in neurons.
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2012-08-01 → 2016-07-31
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-CIG
Линиите свързват координатора с партньорите.
Накратко на български
Протеинът миозин VI транспортира AMPA рецептори в невроните, което е важно за предаването на сигнали в мозъка. Разбирането на този механизъм помага да се разбере как работят синапсите и как се влияе върху двигателното обучение.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Uncovering the mechanism and physiological relevance of myosin-VI-dependent AMPA receptor trafficking in neurons.
The cellular mechanisms that govern synaptic function and development in the nervous system are still incompletely understood. We aim to shed light on these mechanisms by dissecting the role of myosin VI in the transport of neurotransmitter receptors. Myosin VI is a cytoskeletal motor that moves towards the minus end of the actin filament and that is involved in intracellular membrane trafficking events such as clathrin-mediated endocytosis, exocytosis and autophagy. Moreover, myosin VI is implicated in the trafficking of AMPA receptors which are crucial neurotransmitter receptors that mediate fast neurotransmission at excitatory synapses. Our objectives in the project comprised to uncover the precise mechanism via which the myosin affects AMPA receptor trafficking. Moreover, we aimed to determine the significance of neuronal myosin VI for synaptic function and plasticity and for cerebellar motor learning. To address these points, we made use of Snell's waltzer mice that carry a functional null allele of Myo6, the gene encoding the myosin VI heavy chain. Our data show that AMPA receptor-mediated synaptic transmission and synaptic plasticity are impaired in cerebellar Purkinje cells of these mice. This suggests that myosin VI-dependent AMPA receptor trafficking in Purkinje cells is crucial for synaptic function. Using mice that carry a conditional knockout of the myosin, we tested whether this protein is required in Purkinje cells for motor learning and coordination. Our data currently suggest that this is not the case. To obtain insight into how myosin VI might act in regulating synaptic AMPA receptor numbers in Purkinje cells, we characterized its cellular and subcellular localization in brain. Furthermore, we developed novel tools that allow us to investigate which of the myosin's biophysical properties and protein interactions are crucial for AMPA receptor trafficking in neurons. In summary, our findings shed new light on the mechanisms that regulate synaptic function and emphasize the relevance of myosins in this fundamentally important process.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
The proper trafficking of membranes and associated proteins in neurons is crucial for the function of the nervous system. Myosin-VI is an actin-based cytoskeletal motor that promotes membrane trafficking and is suggested to play crucial roles in neurons. Most notably, the myosin affects the intracellular trafficking of AMPA receptors, major neurotransmitter receptors composed of transmembrane protein subunits. In addition, data suggest a potential link between myosin-VI and neurodegenerative diseases such as Alzheimer’s. Here, we want to dissect the molecular mechanism by which myosin-VI acts in AMPA receptor trafficking in neurons. Furthermore, we aim to determine the relevance of myosin-VI-driven AMPA receptor trafficking events for structure, function and plasticity of a well-characterized neuronal circuit, and for behavioral output. To this end, we will focus on Purkinje neurons as a model system. These cerebellar neurons are crucial for the coordination and fine-tuning of movements and for certain forms of motor learning. We will make use of genetically altered mice in combination with approaches such as transfection and live cell microscopy of cultured Purkinje neurons, in vitro genetic rescue experiments, ultra-structural analyses via electron microscopy, electrophysiological methods and behavioral tests. We expect that our study will provide novel, general insights into the mechanism by which myosin-VI functions in membrane trafficking. In particular, the results should shed new light onto the molecular and cellular events that take place in Purkinje neurons and determine output from the cerebellum. Moreover, understanding the mechanism of function of neuronal myosin-VI might impact our view of the pathogenesis of neurodegenerative disease.
Оригинален текст от CORDIS (на английски).
Участници
- UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF · HamburgКоординаторГермания
Връзки
Данни: CORDIS, © Европейски съюз