Loss of the Drosophila m-AAA mitochondrial protease paraplegin results in mitochondrial dysfunction, shortened lifespan, and neuronal and muscular degeneration.
Loss of the Drosophila m-AAA mitochondrial protease paraplegin results in mitochondrial dysfunction, shortened lifespan, and neuronal and muscular degeneration.
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DOI：
10.1038/s41419-018-0365-8
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发表时间：
2018-02-21
影响因子：
9
通讯作者：
Pallanck LJ
中科院分区：
文献类型：
--
作者：
Pareek G;Thomas RE;Pallanck LJ
功能障碍性线粒体的进行性积累与衰老和老年人的常见疾病有关。为了对抗这种情况，生物体采用了各种策略，包括选择性降解氧化损伤和错误折叠的线粒体蛋白。酵母中的遗传研究表明，线粒体蛋白酶的与多种细胞活性相关的ATP酶（AAA+）家族占这种蛋白质降解的很大一部分，但是它们的后生动物对应物很少被研究，尽管编码这些蛋白酶的基因突变导致多种人类疾病。为了开始探索后生动物线粒体AAA+蛋白酶家族的生物学作用，我们已经创建了SPG 7的果蝇同源物的CRISPR/Cas9等位基因，其编码被称为paraplegin的内膜定位的AAA+蛋白酶。果蝇SPG 7突变体表现出寿命缩短，进行性运动缺陷，对化学和环境应激敏感，肌肉和神经元变性。感光神经元的超微结构检查表明，SPG 7突变体的神经退行性表型在突触末端启动。各种线粒体缺陷伴随着SPG 7突变体的退行性表型，包括改变轴突运输的线粒体，积累的电子致密物质在飞行肌线粒体的基质中，减少活动的呼吸链复合物I和II，和严重肿胀和畸形的光感受器的突触末端的线粒体。果蝇SPG 7突变体概括了由SPG 7突变引起的人类疾病的关键特征，从而为鉴定果蝇paraplegin底物和可用于改善这些疾病症状的策略提供了基础。
The progressive accumulation of dysfunctional mitochondria is implicated in aging and in common diseases of the elderly. To oppose this occurrence, organisms employ a variety of strategies, including the selective degradation of oxidatively damaged and misfolded mitochondrial proteins. Genetic studies in yeast indicate that the ATPase Associated with diverse cellular Activities (AAA+) family of mitochondrial proteases account for a substantial fraction of this protein degradation, but their metazoan counterparts have been little studied, despite the fact that mutations in the genes encoding these proteases cause a variety of human diseases. To begin to explore the biological roles of the metazoan mitochondrial AAA+ protease family, we have created a CRISPR/Cas9 allele of the Drosophila homolog of SPG7, which encodes an inner membrane-localized AAA+ protease known as paraplegin. Drosophila SPG7 mutants exhibited shortened lifespan, progressive locomotor defects, sensitivity to chemical and environmental stress, and muscular and neuronal degeneration. Ultrastructural examination of photoreceptor neurons indicated that the neurodegenerative phenotype of SPG7 mutants initiates at the synaptic terminal. A variety of mitochondrial defects accompanied the degenerative phenotypes of SPG7 mutants, including altered axonal transport of mitochondria, accumulation of electron-dense material in the matrix of flight muscle mitochondria, reduced activities of respiratory chain complexes I and II, and severely swollen and dysmorphic mitochondria in the synaptic terminals of photoreceptors. Drosophila SPG7 mutants recapitulate key features of human diseases caused by mutations in SPG7, and thus provide a foundation for the identification of Drosophila paraplegin substrates and strategies that could be used to ameliorate the symptoms of these diseases.
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影响因子：
1.2
作者：
Babcock, Daniel T.;Ganetzky, Barry
通讯作者：
Ganetzky, Barry
影响因子：
2.5
作者：
Borycz, JA;Borycz, J;Meinertzhagen, IA
通讯作者：
Meinertzhagen, IA
影响因子：
12.4
作者：
Hwang, M-S;Schwall, C. T.;Grimm, S.
通讯作者：
Grimm, S.
影响因子：
64.8
作者：
Clark, Ira E.;Dodson, Mark W.;Guo, Ming
通讯作者：
Guo, Ming
影响因子：
9.8
作者：
Jenkinson, Emma M.;Rehman, Atteeq U.;Newman, William G.
通讯作者：
Newman, William G.