LRRK2 G2019S is a common mutation in Spanish patients with late-onset Parkinson's disease

The Excitatory Amino Acid Transporter 2 (EAAT2) accounts for 80% of brain glutamate clearance and is mainly expressed in astrocytic perisynaptic processes. EAAT2 function is finely regulated by endocytic events, recycling to the plasma membrane and degradation. Noteworthy, deficits in EAAT2 have been associated with neuronal excitotoxicity and neurodegeneration. In this study, we show that EAAT2 trafficking is impaired by the leucine-rich repeat kinase 2 (LRRK2) pathogenic variant G2019S, a common cause of late-onset familial Parkinson's disease (PD). In LRRK2 G2019S human brains and experimental animal models, EAAT2 protein levels are significantly decreased, which is associated with elevated gliosis. The decreased expression of the transporter correlates with its reduced functionality in mouse LRRK2 G2019S purified astrocytic terminals and in Xenopus laevis oocytes expressing human LRRK2 G2019S. In Lrrk2 G2019S knockin mouse brain, the correct surface localization of the endogenous transporter is impaired, resulting in its interaction with a plethora of endo-vesicular proteins. Mechanistically, we report that pathogenic LRRK2 kinase activity delays the recycling of the transporter to the plasma membrane, causing its intracellular relocalization and degradation. Taken together, our results demonstrate that pathogenic LRRK2 interferes with the physiology of EAAT2, pointing to extracellular glutamate overload as a possible contributor to neurodegeneration in PD.

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Protein synthesis is suppressed in sporadic and familial Parkinson’s Disease by LRRK2

10.1101/2020.04.27.053694 ◽

2020 ◽

Author(s):

Prasannakumar Deshpande ◽

Dani Flinkman ◽

Ye Hong ◽

Elena Goltseva ◽

Valentina Siino ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Protein Synthesis ◽

Gene Knockout ◽

Common Mutation ◽

Pathological Mechanism ◽

Lrrk2 Gene ◽

Lrrk2 G2019s ◽

Sporadic Parkinson’S Disease ◽

Or Gene

ABSTRACTGain of function LRRK2-G2019S is the most common mutation associated with both familial and sporadic Parkinson’s disease. It is expected therefore that understanding the cellular function of LRRK2 will provide much needed insight on the pathological mechanism of sporadic Parkinson’s, which is the most common form. Here we show that constitutive LRRK2 activity represses nascent protein synthesis in rodent neurons. Specifically, enzymatic inhibition of LRRK2, gene silencing or gene knockout of Lrrk2 increase translation. In the rotenone model of Parkinson’s, LRRK2 activity increases, leading to repression of translation and dopaminergic neuron atrophy both of which are prevented by LRRK2 inhibition. This is accompanied by altered phosphorylation of eIF2α-S52(↑), eIF2s2-S2(↓) and eEF2-T57(↑) in striatum/substantia nigra in a direction that signifies inhibition of protein synthesis. Significantly, LRRK2 is activated and translation is 40% reduced in Parkinson’s patient fibroblasts (G2019S and sporadic) and LRRK2 inhibition restores normal translation. In contrast, translation is unchanged in cells from multiple system atrophy patients, implying disease specificity. These findings suggest that LRRK2-dependent repression of translation may be a proximal function of LRRK2 in Parkinson’s pathology.

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Neuronal hyperactivity in a LRRK2-G2019S cellular model of Parkinson's Disease

10.1101/2021.06.23.449591 ◽

2021 ◽

Author(s):

Edinson Lucumi Moreno ◽

Siham Hachi ◽

Sarah L Nickels ◽

Kalid IW Kane ◽

Masha Moein ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuronal Activity ◽

Late Onset ◽

Induced Pluripotent Stem Cell ◽

Calcium Transient ◽

Lrrk2 Gene ◽

Lrrk2 G2019s ◽

Induced Pluripotent

Monogenic Parkinson's Disease can be caused by a mutation in the leucine-rich repeat kinase 2 (LRRK2) gene, causing a late-onset autosomal dominant inherited form of Parkinson's Disease. The function of the LRRK2 gene is incompletely understood, but several in vitro studies have reported that LRRK2-G2019S mutations affect neurite branching, calcium homeostasis and mitochondrial function, but thus far, there have been no reports of effects on electrophysiological activity. We assessed the neuronal activity of induced pluripotent stem cell derived neurons from Parkinson's Disease patients with LRRK2-G2019S mutations and isogenic controls. Neuronal activity of spontaneously firing neuronal populations was recorded with a fluorescent calcium-sensitive dye (Fluo-4) and analysed with a novel image analysis pipeline that combined semi-automated neuronal segmentation and quantification of calcium transient properties. Compared with controls, LRRK2-G2019S mutants have shortened inter-spike intervals and an increased rate of spontaneous calcium transient induction.

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Faculty Opinions recommendation of A susceptibility gene for late-onset idiopathic Parkinson's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1004442.148857 ◽

2002 ◽

Author(s):

John Hardy

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Late Onset ◽

Susceptibility Gene ◽

Idiopathic Parkinson’S Disease ◽

Idiopathic Parkinson's Disease

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Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

Journal of Parkinson s Disease ◽

10.3233/jpd-202421 ◽

2021 ◽

pp. 1-16

Author(s):

Alison Fellgett ◽

C. Adam Middleton ◽

Jack Munns ◽

Chris Ugbode ◽

David Jaciuch ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Genetic Interaction ◽

In Vitro Assays ◽

Rab Proteins ◽

Circadian Activity ◽

Loss Of Function ◽

Lrrk2 G2019s

Background: Inherited mutations in the LRRK2 protein are the common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. Objective: To determine if Rab10 is necessary for LRRK2-induced pathophysiological responses in the neurons that control movement, vision, circadian activity, and memory. These four systems were chosen because they are modulated by dopaminergic neurons in both humans and flies. Methods: LRRK2-G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, retinal neurophysiology, circadian activity pattern (‘sleep’), and courtship memory determined in aged flies. Results: Rab10 loss-of-function rescued LRRK2-G2019S induced bradykinesia and retinal signaling deficits. Rab10 knock-down, however, did not rescue the marked sleep phenotype which results from dopaminergic LRRK2-G2019S. Courtship memory is not affected by LRRK2, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons. Conclusion: We conclude that, in Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson’s disease.

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Identification of sixteen novel candidate genes for late onset Parkinson’s disease

Molecular Neurodegeneration ◽

10.1186/s13024-021-00455-2 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Alessandro Gialluisi ◽

Mafalda Giovanna Reccia ◽

Nicola Modugno ◽

Teresa Nutile ◽

Alessia Lombardi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Candidate Genes ◽

Rare Variants ◽

Late Onset ◽

High Specificity ◽

Diagnostic Tools ◽

Multi Stage ◽

Whole Exome ◽

Family Based

Abstract Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.

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Contribution of coding/non-coding variants in NUS1 to late-onset sporadic Parkinson's disease

Parkinsonism & Related Disorders ◽

10.1016/j.parkreldis.2021.01.014 ◽

2021 ◽

Vol 84 ◽

pp. 29-34

Author(s):

Li Jiang ◽

Hong-xu Pan ◽

Yu-wen Zhao ◽

Qian Zeng ◽

Zhen-hua Liu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Late Onset ◽

Sporadic Parkinson’S Disease ◽

Coding Variants

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A susceptibility gene for late-onset idiopathic Parkinson's disease

Annals of Neurology ◽

10.1002/ana.10324 ◽

2002 ◽

Vol 52 (5) ◽

pp. 549-555 ◽

Cited By ~ 196

Author(s):

Andrew A. Hicks ◽

Hjörvar Pétursson ◽

Thorlákur Jónsson ◽

Hreinn Stefánsson ◽

Hrefna S. Jóhannsdóttir ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Late Onset ◽

Susceptibility Gene ◽

Idiopathic Parkinson’S Disease ◽

Idiopathic Parkinson's Disease

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A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels

International Journal of Molecular Sciences ◽

10.3390/ijms22073708 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3708

Author(s):

Jun Ogata ◽

Kentaro Hirao ◽

Kenya Nishioka ◽

Arisa Hayashida ◽

Yuanzhe Li ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Peripheral Blood ◽

Kinase Activity ◽

Late Onset ◽

Causative Gene ◽

Protein Levels ◽

Wd40 Domain ◽

Lrrk2 Protein ◽

Familial Parkinson’S Disease

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.

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The universal non-neuronal nature of Parkinson's disease: A theory

10.7287/peerj.preprints.1314v1 ◽

2015 ◽

Author(s):

André Valente ◽

Altynay Adilbayeva ◽

Tursonjan Tokay ◽

Albert Rizvanov

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dna ◽

Late Onset ◽

Clinical Signs ◽

Global Gene Expression ◽

Neuron Death ◽

Hematopoietic Stem ◽

Hematopoietic Stem Cell Niche

Various recent developments of relevance to Parkinson's disease (PD) are discussed and integrated into a comprehensive hypothesis on the nature, origin and inter-cellular mode of propagation of late-onset sporadic PD. We propose to define sporadic PD as a characteristic pathological deviation in the global gene expression program of a cell: the PD expression-state, or PD-state for short. Although a universal cell-generic state, the PD-state deviation would be particularly damaging in a neuronal context, ultimately leading to neuron death and the ensuing observed clinical signs. We review why age accumulated damage caused by oxidative stress in mitochondria could be the trigger for a primordial cell to shift to the PD-state. We put forward hematopoietic cells could be the first to acquire the PD-state, at hematopoiesis, from the disruption in reactive oxygen species (ROS) homeostasis that arises with age in the hematopoietic stem-cell niche. We argue why, nonetheless, such a process is unlikely to explain the shift to the PD-state of all the subsequently affected cells in a patient, thus indicating the existence of a distinct mechanism of propagation of the PD-state. We highlight recent findings on the intercellular exchange of mitochondrial DNA and the ability of mitochondrial DNA to modulate the cellular global gene expression state and propose this could form the basis for the intercellular propagation of the PD-state.

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