Mitochondrial Mechanisms of LRRK2 G2019S Penetrance.

Sylvie Delcambre,Anne Grünewald,Nassima Ouzren,Jenny Ghelfi,Jan O Aasly,Léa Grandmougin,Christine Klein,Joanne Trinh,Catherine Delbrouck,Philip Seibler,Kobi Wasner,Sandro L Pereira

doi:10.3389/fneur.2020.00881

Abstract

Several mutations in leucine-rich repeat kinase-2 (LRRK2) have been associated with Parkinson's disease (PD). The most common substitution, G2019S, interferes with LRRK2 kinase activity, which is regulated by autophosphorylation. Yet, the penetrance of this gain-of-function mutation is incomplete, and thus far, few factors have been correlated with disease status in carriers. This includes (i) LRRK2 autophosphorylation in urinary exosomes, (ii) serum levels of the antioxidant urate, and (iii) abundance of mitochondrial DNA (mtDNA) transcription-associated 7S DNA. In light of a mechanistic link between LRRK2 kinase activity and mtDNA lesion formation, we previously investigated mtDNA integrity in fibroblasts from manifesting (LRRK2+/PD+) and non-manifesting carriers (LRRK2+/PD−) of the G2019S mutation as well as from aged-matched controls. In our published study, mtDNA major arc deletions correlated with PD status, with manifesting carriers presenting the highest levels. In keeping with these findings, we now further explored mitochondrial features in fibroblasts derived from LRRK2+/PD+ (n = 10), LRRK2+/PD− (n = 21), and control (n = 10) individuals. In agreement with an accumulation of mtDNA major arc deletions, we also detected reduced NADH dehydrogenase activity in the LRRK2+/PD+ group. Moreover, in affected G2019S carriers, we observed elevated mitochondrial mass and mtDNA copy numbers as well as increased expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates antioxidant signaling. Taken together, these results implicate mtDNA dyshomeostasis—possibly as a consequence of impaired mitophagy—in the penetrance of LRRK2-associated PD. Our findings are a step forward in the pursuit of unveiling markers that will allow monitoring of disease progression of LRRK2 mutation carriers.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disorder with a prevalence of 1% over the age of 60 years old [1]
We have recently reported that the accumulation of mitochondrial DNA (mtDNA) deletions serves as a discriminator between affected and unaffected leucine-rich repeat kinase 2 (LRRK2) mutation carriers [18]
There is a myriad of biological pathways implicated in LRRK2dependent neurodegeneration including cytoskeletal dynamics, autophagy, trafficking, and mitochondrial dysfunction [1]

Summary

INTRODUCTION

Parkinson’s disease (PD) is the second most common neurodegenerative disorder with a prevalence of 1% over the age of 60 years old [1]. Altered respiratory chain function coinciding with increased oxidative stress and morphological changes has been observed in cellular models of LRRK2-PD [10]. In the presence of the G2019S mutation, mitochondrial DNA (mtDNA) lesions accumulate in patient-derived neurons [11]—a process that can be reversed by kinase inhibitor treatment [12]. The assessment of LRRK2 phosphorylation rates in urinary exosomes revealed higher levels in manifesting (LRRK2+/PD+) compared to non-manifesting (LRRK2+/PD−) individuals harboring the common G2019S mutation in LRRK2 [13]. Our own research previously demonstrated an increase in the mitochondrial reactive oxygen species (ROS) scavenger superoxide dismutase (SOD)2 [17] and an accumulation of somatic mtDNA major arc deletions in fibroblasts from LRRK2+/PD+ compared to LRRK2+/PD− individuals [18]. Extending the mtDNA integrity and oxidative stress analyses, we assessed mtDNA abundance as well as functional parameters such as transcriptional and respiratory chain complex activities

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DISCUSSION

ETHICS STATEMENT