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

We investigate in larval and adult Drosophila models whether loss of the mitochondrial chaperone Hsc70-5 / mortalin 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 study 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 displays ATP depletion, altered body posture, and susceptibility to heat-induced paralysis. Adult phenotypes could be suppressed by knockdown of DJ-1b, LRRK, p50, p150, Atg1, Atg101, Atg5, Atg7 , and Atg12 . The knockdown of components of the autophagy machinery or overexpression of human mortalin broadly rescued larval and adult phenotypes, while disease-associated HSPA9 variants did not. Overexpression of Pink1 or promotion of autophagy exacerbated defects. ### Competing Interest Statement The authors have declared no competing interest. * AEL : after egg laying AZ : active zone Brp : Bruchpilot CSP : cysteine string protein DLG : discs large eEJPs : evoked excitatory junctional potentials GluR : glutamate receptor 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