Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5 in Drosophila.
Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5 in Drosophila.
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DOI：
10.1080/15548627.2020.1871211
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发表时间：
2021-10
期刊：
影响因子：
13.3
通讯作者：
Rasse TM
中科院分区：
文献类型：
--
作者：
Zhu JY;Hannan SB;Dräger NM;Vereshchagina N;Krahl AC;Fu Y;Elliott CJH;Han Z;Jahn TR;Rasse TM
我们在果蝇幼虫和成虫模型中研究了线粒体伴侣Hsc 70 -5的丢失是否足以引起帕金森病中常见的病理改变。在受影响的幼虫神经肌肉接头，终端的大小，终扣的大小或数量，突触的大小，或数量没有影响进行了观察，这表明我们研究了发病机制的早期阶段。在这个阶段，我们注意到突触囊泡蛋白和活性区成分的损失，延迟突触成熟，降低诱发和自发兴奋性连接电位，增加突触疲劳，和细胞骨架重排。成年模型显示ATP耗竭，改变了身体姿势，并对热诱导的瘫痪易感。通过敲低dj-1β、Lrrk、DCTN 2-p50、DCTN 1-p150、Atg 1、Atg 101、Atg 5、Atg 7和Atg 12可以抑制成体表型。敲低大自噬/自噬机制的组分或人HSPA 9的过表达广泛地挽救了幼虫和成虫的表型，而疾病相关的HSPA 9变体则没有。Pink 1的过度表达或促进自噬加重了缺陷。缩略语：AEL：产蛋后; AZ：活动带brp：bruchpilot; CSP：半胱氨酸串蛋白; dlg：花盘大; eEJP：诱发兴奋性连接电位; GluR：谷氨酸受体; H2 O2：过氧化氢; mEJP：微型兴奋性连接电位; MT：微管; NMJ：神经肌肉接头; PD：帕金森病; Pink 1：PTEN诱导的推定激酶1; PSD：突触后密度; SSR：突触下网状结构; SV：突触囊泡; VGlut：囊泡谷氨酸转运蛋白。
We investigated in larval and adult Drosophila models whether loss of the mitochondrial chaperone Hsc70-5 is sufficient to cause pathological alterations commonly observed in Parkinson disease. At affected larval neuromuscular junctions, no effects on terminal size, bouton size or number, synapse size, or number were observed, suggesting that we studied an early stage of pathogenesis. At this stage, we noted a loss of synaptic vesicle proteins and active zone components, delayed synapse maturation, reduced evoked and spontaneous excitatory junctional potentials, increased synaptic fatigue, and cytoskeleton rearrangements. The adult model displayed ATP depletion, altered body posture, and susceptibility to heat-induced paralysis. Adult phenotypes could be suppressed by knockdown of dj-1β, Lrrk, DCTN2-p50, DCTN1-p150, Atg1, Atg101, Atg5, Atg7, and Atg12. The knockdown of components of the macroautophagy/autophagy machinery or overexpression of human HSPA9 broadly rescued larval and adult phenotypes, while disease-associated HSPA9 variants did not. Overexpression of Pink1 or promotion of autophagy exacerbated defects. Abbreviations: AEL: after egg laying; AZ: active zone; brp: bruchpilot; Csp: cysteine string protein; dlg: discs large; eEJPs: evoked excitatory junctional potentials; GluR: glutamate receptor; H2O2: hydrogen peroxide; mEJP: miniature excitatory junctional potentials; MT: microtubule; NMJ: neuromuscular junction; PD: Parkinson disease; Pink1: PTEN-induced putative kinase 1; PSD: postsynaptic density; SSR: subsynaptic reticulum; SV: synaptic vesicle; VGlut: vesicular glutamate transporter.
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影响因子：
4.5
作者：
Füger P;Sreekumar V;Schüle R;Kern JV;Stanchev DT;Schneider CD;Karle KN;Daub KJ;Siegert VK;Flötenmeyer M;Schwarz H;Schöls L;Rasse TM
通讯作者：
Rasse TM
影响因子：
5.6
作者：
Dagda RK;Das Banerjee T;Janda E
通讯作者：
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影响因子：
9
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影响因子：
4.8
作者：
Devi, Latha;Raghavendran, Vijayendran;Anandatheerthavarada, Hindupur K.
通讯作者：
Anandatheerthavarada, Hindupur K.
影响因子：
5.1
作者：
Janda, Elzbieta;Isidoro, Ciro;Mollace, Vincenzo
通讯作者：
Mollace, Vincenzo