Pharmacological rescue of impaired mitophagy in Parkinson's disease-related LRRK2 G2019S knock-in mice.

Graeme Ball,Ian G Ganley,Francois Singh,Alastair D Reith,Alan R Prescott,Philippa Rosewell

doi:10.7554/elife.67604

Abstract

Parkinson's disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation - key features of the autophagy of mitochondria, known as mitophagy. Here, we investigated the role of LRRK2, a protein kinase frequently mutated in PD, in this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues. Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice. This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic Parkinson's disease, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting 1-2% of the population over 60 years old, and 4% above 85 years of age 1
Given that mitophagy is a form of autophagy, the use of both models allows us to monitor the specificity of autophagy in vivo
Our work reveals that Leucine-rich repeat kinase 2 (LRRK2) kinase activity inversely correlates with basal mitophagy levels, both in vitro and in vivo in specific cells and tissues

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting 1-2% of the population over 60 years old, and 4% above 85 years of age 1. The main symptoms of PD are muscle rigidity, bradykinesia, resting tremor, and postural instability and may be accompanied by sleep disorders, anosmia, depression, and dementia 2. It is characterised by a progressive and selective degeneration of dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). There are no treatments available that modify the course of neurodegenerative decline. This disease is mostly sporadic, about 15% of cases appear to be inherited and in support of this, 20 genes implicated in PD have been identified from familial genetic studies while ~90 loci have been identified from PD-GWAS 3. The exact causes of PD are currently unknown but some evidence strongly links impaired mitochondrial and lysosomal function to disease pathology 2

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