Mitochondrial Mechanisms of LRRK2 G2019S Penetrance

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

doi:10.3389/fneur.2020.00881

Cited by 26 publications

(27 citation statements)

References 30 publications

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“…Although we failed to detect an effect of LRRK2 inhibition of global cellular mitochondrial respiration, it is possible a small pool of mitochondria has altered oxygen consumption that impacts mitophagy. Indeed, deleterious mitochondrial phenotypes have been observed in LRRK2 G2019S patient-derived cells ( Delcambre et al, 2020 ; Mortiboys et al, 2010 ; Sanders et al, 2014 ), although further work is needed to clarify if this is a cause or consequence of impaired mitophagy. It is important to note that GSK3357679A led to activation of mitochondrial biogenesis via PGC-1β and not PGC-1α.…”

Section: Discussionmentioning

confidence: 99%

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

Singh

Prescott

Rosewell

et al. 2021

eLife

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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.

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Section: Discussionmentioning

confidence: 99%

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

Singh

Prescott

Rosewell

et al. 2021

eLife

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“…Coding variants in LRRK2 leading to PD segregate to its catalytic core, such as in the GTPase domain (R1441C/G/H or Y1699C) and in its kinase domain (G2019S and I2020T). The G2019S mutation being the most frequent genetic cause of PD, representing 4–5% of familial cases and about 1% of sporadic cases [ 88 ]. All the known pathogenic mutations of LRRK2 lead to an increased kinase activity [ 89 ].…”

Section: Lrrk2 and Basal Mitophagymentioning

confidence: 99%

“…Work has shown that patient-derived fibroblasts from G2019S carriers display abnormal mitochondrial morphology and function [ 92 ]. Likewise, this same LRRK2 mutation has been shown to increase mitochondrial DNA damage in human-derived cells [ 88 , 93 ]. The abnormal mitochondrial phenotype is also present in mice with aged G2019S knock-in animals displaying hallmarks of impaired fission and altered dynamics [ 94 , 95 ].…”

Section: Lrrk2 and Basal Mitophagymentioning

confidence: 99%

Parkinson's disease and mitophagy: an emerging role for LRRK2

Singh

Ganley

2021

Biochemical Society Transactions

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Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiffness. Its aetiology is poorly understood as the physiological and molecular mechanisms leading to this neuronal loss are currently unclear. However, mitochondrial and lysosomal dysfunction seem to play a central role in this disease. In recent years, defective mitochondrial elimination through autophagy, termed mitophagy, has emerged as a potential contributing factor to disease pathology. PINK1 and Parkin, two proteins mutated in familial PD, were found to eliminate mitochondria under distinct mitochondrial depolarisation-induced stress. However, PINK1 and Parkin are not essential for all types of mitophagy and such pathways occur in most cell types and tissues in vivo, even in the absence of overt mitochondrial stress — so-called basal mitophagy. The most common mutation in PD, that of glycine at position 2019 to serine in the protein kinase LRRK2, results in increased activity and this was recently shown to disrupt basal mitophagy in vivo. Thus, different modalities of mitophagy are affected by distinct proteins implicated in PD, suggesting impaired mitophagy may be a common denominator for the disease. In this short review, we discuss the current knowledge about the link between PD pathogenic mutations and mitophagy, with a particular focus on LRRK2.

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“…For example, at the age of 60 years, 60% of Tunisian p.G2019S pathogenic variant carriers manifest PD, compared with only 20% of the Norwegian carriers of the same pathogenic variant ( 4 ). Recent studies have suggested mitochondrial involvement in the penetrance of LRRK2 -linked PD ( 5 , 6 ). Environmental factors can also influence penetrance, as recently found in the Tunisian Arab Berber population, where tobacco and black tea use delayed age at onset in LRRK2 pathogenic variant carriers ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

“…Recently published data from the currently largest multinational prospective study that includes LRRK2 pathogenic variant carriers, i.e., the Parkinson's Progression Markers Initiative (PPMI), provide more phenotypic details on LRRK2 pathogenic variant carriers across international sites ( 6 ). However, as the focus of the PPMI study is predominantly on biomarkers, it does not cover environmental factors in-depth, and only includes participants with a PD diagnosis 2 years or less before enrolment who are untreated with PD medication.…”

Section: Introductionmentioning

confidence: 99%

LIPAD (LRRK2/Luebeck International Parkinson's Disease) Study Protocol: Deep Phenotyping of an International Genetic Cohort

et al. 2021

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Background: Pathogenic variants in the Leucine-rich repeat kinase 2 (LRRK2) gene are the most common known monogenic cause of Parkinson's disease (PD). LRRK2-linked PD is clinically indistinguishable from idiopathic PD and inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity that differ across ethnicities and geographic regions.Objective: To systematically assess clinical signs and symptoms including non-motor features, comorbidities, medication and environmental factors in PD patients, unaffected LRRK2 pathogenic variant carriers, and controls. A further focus is to enable the investigation of modifiers of penetrance and expressivity of LRRK2 pathogenic variants using genetic and environmental data.Methods: Eligible participants are invited for a personal or online examination which comprises completion of a detailed eCRF and collection of blood samples (to obtain DNA, RNA, serum/plasma, immune cells), urine as well as household dust. We plan to enroll 1,000 participants internationally: 300 with LRRK2-linked PD, 200 with LRRK2 pathogenic variants but without PD, 100 PD patients with pathogenic variants in the GBA or PRKN genes, 200 patients with idiopathic PD, and 200 healthy persons without pathogenic variants.Results: The eCRF consists of an investigator-rated (1 h) and a self-rated (1.5 h) part. The first part includes the Movement Disorder Society Unified Parkinson's Disease Rating, Hoehn &Yahr, and Schwab & England Scales, the Brief Smell Identification Test, and Montreal Cognitive Assessment. The self-rating part consists of a PD risk factor, food frequency, autonomic dysfunction, and quality of life questionnaires, the Pittsburgh Sleep Quality Inventory, and the Epworth Sleepiness as well as the Hospital Anxiety and Depression Scales. The first 15 centers have been initiated and the first 150 participants enrolled (as of March 25th, 2021).Conclusions: LIPAD is a large-scale international scientific effort focusing on deep phenotyping of LRRK2-linked PD and healthy pathogenic variant carriers, including the comparison with additional relatively frequent genetic forms of PD, with a future perspective to identify genetic and environmental modifiers of penetrance and expressivityClinical Trial Registration:ClinicalTrials.gov, NCT04214509.

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Mitochondrial Mechanisms of LRRK2 G2019S Penetrance

Cited by 26 publications

References 30 publications

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

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

Parkinson's disease and mitophagy: an emerging role for LRRK2

LIPAD (LRRK2/Luebeck International Parkinson's Disease) Study Protocol: Deep Phenotyping of an International Genetic Cohort

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