ParaplegiaAxonsER · Functional interactions between endoplasmic reticulum and mitochondria in Drosophila axons
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2017-03-01 → 2019-02-28
- Финансиране от ЕС
- 183 455 €
- Участници
- 1
- Схема
- MSCA-IF-EF-ST
Линиите свързват координатора с партньорите.
Накратко на български
Взаимодействията между ендоплазматичния ретикулум и митохондриите се проучват чрез наблюдение на нивата на калций в неврони на плодови мухи. Това помага да се разбере как определени генетични мутации водят до дегенерация на двигателните неврони при наследствените спастични параплегии.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Functional interactions between endoplasmic reticulum and mitochondria in Drosophila axons
Hereditary Spastic Paraplegias (HSPs) are a group of disorders characterised by lower limb spasticity and weakness, caused by selective degeneration of motor neurons. Whilst there are many genes implicated in HSP, the most commonly mutated group of genes are those involved in shaping the membrane of a specialised intracellular compartment, the endoplasmic reticulum (ER). The ER is critical in maintaining homeostasis within the cell, constantly sensing and relaying information in every part of the neuron. One key feature of the ER is its continuity, it invades every part of the cell through a network of sheets and tubules, which is key for its communication. Using Drosophila (fruit fly) as a model organism we disrupted several HSP genes that have been identified in humans, and observed that the integrity and continuity of the ER was perturbed in the longest motor neurons, analogous to the human condition [1]. To understand the functional consequences of this disruption, and learn more about how these mutations might lead to neurodegenerative disease, we needed to develop tools to interrogate this. One of the main ways in which the ER communicates, within itself and with other organelles, is with calcium ions. Therefore I aimed to develop fluorescent calcium sensors for use in Drosophila, targeted to the interior (lumen) of ER tubules, to monitor changes in the level of calcium. Together with sensors in other subcellular compartments (mitochondria, cytoplasm and post-synapse), I planned to interrogate changes to calcium handling in HSP-mutant flies.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Axonal endoplasmic reticulum (ER) forms a continuous network of tubules that appears to occur ubiquitously in neurons, and has been compared to “a neuron within a neuron”. Its importance is suggested both by its apparent ubiquity, and by the identification of several causative genes for the axon degenerative disease, hereditary spastic paraplegia (HSP), that encode proteins that contribute to ER modeling. However, its physiological roles, and how it could influence axon degeneration, are poorly understood. There is increasing awareness of the existence, nature and roles of contact sites between ER and other cellular organelles including mitochondria. Here I will explore these interactions and their functions in axons, in particular testing the model that ER architecture is important in regulating mitochondrial function in axons. My host laboratory has recently identified Drosophila mutants that lack one or more relevant HSP genes, and shown abnormalities in the level or continuity of ER in some genotypes.I will use Drosophila HSP mutants to determine whether mitochondrial abnormalities arise with altered ER organisation. I will also test for colocalisation of a Drosophila Reep protein with ER-mitochondrial contact sites, and whether loss of this protein leads to abnormal mitochondria. Together these experiments will address whether ER-localised HSP proteins affect mitochondrial function.Secondly I will examine whether mitochondrial Ca2+ handling is affected in these models. I will generate transgenic Drosophila that express mitochondrial and cytosolic Ca2+ sensors, and attempt to develop a suitable lumenal ER sensor. I will use these to test the levels and heterogeneity of Ca2+ concentrations in resting and active axons, and investigate how HSP mutants affect this.My work will examine the interplay between ER and mitochondria in axons for the first time, and mechanisms of dysfunction that are relevant for human axon degeneration.
Оригинален текст от CORDIS (на английски).
Участници
- THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGEКоординаторОбединеното кралство
Връзки
Данни: CORDIS, © Европейски съюз