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Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5 in Drosophila

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 si...

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Autores principales: Zhu, Jun-yi, Hannan, Shabab B., Dräger, Nina M., Vereshchagina, Natalia, Krahl, Ann-Christin, Fu, Yulong, Elliott, Christopher J.H., Han, Zhe, Jahn, Thomas R., Rasse, Tobias M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526020/
https://www.ncbi.nlm.nih.gov/pubmed/33404278
http://dx.doi.org/10.1080/15548627.2020.1871211
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author Zhu, Jun-yi
Hannan, Shabab B.
Dräger, Nina M.
Vereshchagina, Natalia
Krahl, Ann-Christin
Fu, Yulong
Elliott, Christopher J.H.
Han, Zhe
Jahn, Thomas R.
Rasse, Tobias M.
author_facet Zhu, Jun-yi
Hannan, Shabab B.
Dräger, Nina M.
Vereshchagina, Natalia
Krahl, Ann-Christin
Fu, Yulong
Elliott, Christopher J.H.
Han, Zhe
Jahn, Thomas R.
Rasse, Tobias M.
author_sort Zhu, Jun-yi
collection PubMed
description 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; H(2)O(2): 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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spelling pubmed-85260202021-10-20 Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5 in Drosophila Zhu, Jun-yi Hannan, Shabab B. Dräger, Nina M. Vereshchagina, Natalia Krahl, Ann-Christin Fu, Yulong Elliott, Christopher J.H. Han, Zhe Jahn, Thomas R. Rasse, Tobias M. Autophagy Research Paper 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; H(2)O(2): 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. Taylor & Francis 2021-01-25 /pmc/articles/PMC8526020/ /pubmed/33404278 http://dx.doi.org/10.1080/15548627.2020.1871211 Text en © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Paper
Zhu, Jun-yi
Hannan, Shabab B.
Dräger, Nina M.
Vereshchagina, Natalia
Krahl, Ann-Christin
Fu, Yulong
Elliott, Christopher J.H.
Han, Zhe
Jahn, Thomas R.
Rasse, Tobias M.
Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5 in Drosophila
title Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5 in Drosophila
title_full Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5 in Drosophila
title_fullStr Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5 in Drosophila
title_full_unstemmed Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5 in Drosophila
title_short Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5 in Drosophila
title_sort autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone hsc70-5 in drosophila
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526020/
https://www.ncbi.nlm.nih.gov/pubmed/33404278
http://dx.doi.org/10.1080/15548627.2020.1871211
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