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

Jun-Yi Zhu,Shabab B Hannan,Nina M Dräger,Natalia Vereshchagina,Ann-Christin Krahl,Yulong Fu,Christopher J.H Elliott,Zhe Han,Thomas R Jahn,Tobias M Rasse

doi:10.1080/15548627.2020.1871211

Abstract

ABSTRACT 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.

Highlights

Parkinson disease (PD), the most prevalent movement disorder and the second most prevalent neurodegenerative disease, is characterized by resting tremor, stiffness, and slowness of movement
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
Pan-neuronal Hsc70-5 knockdown resulted in severe reductions in mitochondrial mass at neuromuscular junctions (NMJs) of symptomatic but not presymptomatic larvae compared to control (Figure 1B)

Summary

Introduction

Parkinson disease (PD), the most prevalent movement disorder and the second most prevalent neurodegenerative disease, is characterized by resting tremor, stiffness, and slowness of movement. Analysis of genetic and environmental factors contributing to PD suggests that impairments in mitochondrial function, lysosomal degradation pathways, and synaptic transmission are of central importance to pathogenesis and progression of PD [1,2,3,4]. Due to their complex morphology and high-energy demands, neurons in the adult brain are susceptible to dysregulation of mitochondrial quality control systems. While a significant proportion of PD cases are sporadic, mutations in at least 11 genes have been implicated in monogenic typical or atypical forms of parkinsonism [3], providing crucial insights into the cellular and molecular pathways involved in PD. Mitochondrial dysfunctions have been implicated in various other neurodegenerative diseases such as Alzheimer disease where mitochondria are key targets of both Aβ42 and tau toxicity [12]

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Results

Conclusion