The cell-autonomous role of Afg3l2 in mitochondrial dynamics and neurodegeneration

线粒体功能的精细控制在神经元中是必不可少的，正如线粒体功能障碍在神经变性中的致病作用所强调的那样。近年来，线粒体内膜m-AAA线粒体蛋白酶已被证实与人类神经退行性疾病有关。m- AAA蛋白酶降解错误折叠和未组装的多肽，从而在细胞器中进行质量控制监测。此外，它们通过介导必要的加工步骤来调节特定底物的活性。其中之一是线粒体融合分子OPA1，它将线粒体蛋白水解系统和相关的人类疾病与线粒体融合缺陷联系起来。本研究旨在研究m-AAA蛋白酶在介导神经变性和调节线粒体动力学中的细胞自主作用，采用条件小鼠模型Afg3l2，这是m-AAA蛋白酶在大脑中表达的主要亚基。通过在出生后神经元、星形胶质细胞或髓鞘形成细胞中特异性地删除Afg3l2，并通过分析各种模型的神经病理表型，以及对线粒体形态、融合能力、分布、运输和更新的影响，我们希望揭示导致神经退行性变的致病机制和大脑中综合线粒体功能的基本方面。

Fine control of mitochondrial functions is essential in neurons, as underlined by the pathogenic role of mitochondrial dysfunction in neurodegeneration. Recently, m-AAA mitochondrial proteases in the inner mitochondrial membrane have been associated to human neurodegenerative diseases. m- AAA proteases degrade misfolded and non assembled polypeptides, thus performing quality control surveillance in the organelle. Moreover, they regulate the activity of specific substrates by mediating essential processing steps. One of these is the mitochondrial fusion molecule OPA1, linking the mitochondrial proteolytic system and the associated human diseases to defects in mitochondrial fusion. This proposal aims at investigating the cell-autonomous role of the m-AAA protease in mediating neurodegeneration and regulating mitochondrial dynamics, by employing a conditional mouse model of Afg3l2, the main subunit of m-AAA proteases expressed in the brain. By deleting Afg3l2 specifically in postnatal neurons, astrocytes, or myelin forming cells, and by analyzing the neuropathological phenotype of the various models, as well as the effect on mitochondrial morphology, fusion ability, distribution, transport, and turnover, we expect to shed light both on pathogenic mechanisms leading to neurodegeneration and on basic aspects of integrated mitochondrial functions in the brain.