TY  - JOUR
AU  - Zhu, Jun-Yi
AU  - Hannan, Shabab Bin
AU  - Dräger, Nina
AU  - Vereshchagina, Natalia
AU  - Krahl, Ann-Christin
AU  - Fu, Yulong
AU  - Elliott, Christopher J H
AU  - Han, Zhe
AU  - Jahn, Thomas
AU  - Rasse, Tobias
TI  - Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5 in Drosophila.
JO  - Autophagy
VL  - 17
IS  - 10
SN  - 1554-8635
CY  - Abingdon, Oxon
PB  - Taylor & Francis
M1  - DKFZ-2021-00043
SP  - 3160-3174
PY  - 2021
N1  - #LA:B180# /2021 Oct;17(10):3160-3174
AB  - 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.
KW  -  Atg1  (Other)
KW  -  Hsc70-5  (Other)
KW  - microtubule (Other)
KW  - mitochondria (Other)
KW  - mitophagy (Other)
KW  - rapamycin (Other)
KW  - synapse (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:33404278
DO  - DOI:10.1080/15548627.2020.1871211
UR  - https://inrepo02.dkfz.de/record/166690
ER  -