Leucine-rich repeat kinase-2 (LRRK2) modulates microglial phenotype and dopaminergic neurodegeneration

Dwyer, Zach; Rudyk, Chris; Thompson, Abigail; Farmer, Kyle; Fenner, Barbara M.; Fortin, T.; Derksen, Alexa; Sun, Hongyu; Hayley, Shawn; Clint,

doi:10.1016/j.neurobiolaging.2020.02.017

Cited by 36 publications

(28 citation statements)

References 53 publications

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“…knock-in mice in chapter 5, we found that these animals had a heightened vulnerability to sickness, weight loss and had decrease survival following LPS and paraquat treatment. This matches data in LRRK2 knockout animals previously exposed to paraquat which demonstrated protection from these same factors after exposure to either paraquat [298] or LPS and paraquat [415]. Additionally, these G2019S knock-in mice showed basally increased microglial activation, reinforcing the previous findings showing altered microglial motility, ROS production, and cytokine production [82,100,399].…”

Section: Lrrk2 Microglia and Inflammationsupporting

confidence: 88%

“…Data being prepared for publication in our lab has shown that WAVE2 is a downstream target of LRRK2. Indeed, we found that genetic knockout of LRRK2 prevented the morphological and oxidative stress response in microglia [415]. We also found viral overexpression of WAVE2 restored the normal microglial inflammatory response in LRRK2 knockout mice, further supporting a role for WAVE2 in this response.…”

Section: Microglial Phenotype Alterationssupporting

confidence: 59%

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Environmental toxicant exposure and Parkinson’s disease: LRRK2 and inflammatory processes

Dwyer¹

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Parkinson's disease (PD) results from the progressive loss of dopamine producing neurons in the Substantia Nigra pars comapcta (SNc). This loss is thought to occur over several years to decades and current evidence suggests that neuroinflammation may play a central role in this loss. Numerous epidemiological studies have implicated chronic exposure to environmental toxicants such as heavy metals and pesticides to risk of developing PD. Indeed, many of these risk factors have been validated as rodent models of PD, able to induce dopaminergic cell loss in the SNc as well as motor dysfunction. While research strongly supports a role for environmental toxicants and inflammation in PD relatively little work has examined the interactions between these toxicants and other risk factors including senescence, genetic vulnerabilities, the gut microbiota or iii This thesis is based upon the following four manuscripts referred to in text by their corresponding chapter numbers.

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Section: Lrrk2 Microglia and Inflammationsupporting

confidence: 88%

Section: Microglial Phenotype Alterationssupporting

confidence: 59%

Environmental toxicant exposure and Parkinson’s disease: LRRK2 and inflammatory processes

Dwyer¹

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“…Indeed, IFN expression (and LPS injection) alone into the mouse midbrain leads to selective dopaminergic neurodegeneration (Chakrabarty et al, 2011;Mount et al, 2007), while dopamine neurons in the SNpc are well known to be selectively vulnerable to -synuclein over-expression or aggregation. Recent evidence in mouse and rat models suggests LRRK2 knockout diminishes proinflammatory responses to a variety of exogenous stimuli that include LPS, IFN, and adenosine (Dwyer et al, 2020;Hakimi et al, 2011;Kozina et al, 2018;Schapansky et al, 2015). Therefore, anti-inflammatory effects may represent important endpoints to study in clinical evaluation of successful LRRK2-targeting therapeutics, if such effects and cells underlying the effects were better understood.…”

Section: Discussionmentioning

confidence: 99%

“…In cultured mouse macrophages, Lrrk2 deficiency and its kinase inhibition specifically impair chemotaxis without apparent effect on secreted cytokines and chemokines (Levy et al, 2020;Moehle et al, 2015;Moehle et al, 2012;Shutinoski et al, 2019). Recent studies have demonstrated that Lrrk2 knockout or kinase inhibition diminishes innate immune cell responses in the brain, as evidenced by weakened microglial responses to LPS Dwyer et al, 2020;Kim et al, 2012;Ma et al, 2016;Moehle et al, 2012;Russo et al, 2019), to transgenic mutant A53T--synuclein expression , to rAAV2--synuclein expression , to HIV-1 TAT peptide injections (Puccini et al, 2015), and in the context of experimental uveitis (Wandu et al, 2015). Based on these results, LRRK2 has been proposed as a key mediator of innate immune responses in the brain in disease (Russo et al, 2014;Schapansky et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Pathologic α-Synuclein Species Activate LRRK2 in Pro-Inflammatory Monocyte and Macrophage Responses

Boddu

Abdelmotilib

et al. 2020

Preprint

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Missense mutations in the LRRK2 gene that lead to LRRK2 kinase hyperactivity can cause Parkinson's disease (PD). The link between LRRK2 and -synuclein aggregation in PD remains enigmatic. Numerous reports suggest critical LRRK2 functions in microglial responses. Herein, we find that LRRK2-positive immune cells in the brain represent CD68-positive pro-inflammatory, monocyte-derived macrophages, distinct from microglia. Rod -synuclein fibrils stimulate LRRK2 kinase activity in monocyte-derived macrophages, and LRRK2 mutations lead to enhanced recruitment of classical monocytes into the midbrain in response to synuclein. LRRK2 kinase inhibition blocks -synuclein fibril induction of LRRK2 protein in both human and murine macrophages, with human cells demonstrating much higher LRRK2 levels and kinase activity than equivalent murine cells. Further, interferon- strongly induces LRRK2 kinase activity in primary human macrophages in comparison to weak effects observed in murine cells. These results highlight peripheral immune responses in LRRK2-linked paradigms that further connect two central proteins in PD.

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“…If such a connection exists, we contemplate that inhibiting the LRRK2 kinase activity in diagnosed PD patients may have minimal effects since the primary disease-target would have been the initial triggering event. Mechanistically, this could ensue when brain resident microglia respond to an immune trigger by engaging the LRRK2 pathways (via WAVE2) to accommodate a proinflammatory response [51]. The nigrostriatal DA neurons have exceptionally long axons, requiring a high level of energy expenditure, and have therefore been suggested to be particularly vulnerable to challenges affecting mitochondrial function [52,53].…”

Section: Viewpoint -Is Lrrk2 Inhibition In Parkinson's Patients Suffimentioning

confidence: 99%

Precision medicine in Parkinson’s disease patients with LRRK2 and GBA risk variants – Let’s get even more personal

Linstow

Gan‐Or

Brundin

2020

Transl Neurodegener

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Parkinson’s disease (PD) is characterized by motor deficits and a wide variety of non-motor symptoms. The age of onset, rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation. Neuropathologically, the loss of substantia nigra dopaminergic neurons is a key feature of PD. The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions, but there is also great variability in the neuropathology between individuals. While the dopamine replacement therapies can reduce motor symptoms, current therapies do not modify the disease progression. Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification. It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials, and that it is unlikely that a single treatment will be effective in all patients. Precision medicine, using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD, has been suggested as a way forward. PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk. In this review we assess current clinical trials targeting two enzymes, leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA), which are encoded by two most common PD risk genes. Because the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood, we ask if these precision medicine-based intervention strategies will prove “precise” or “personalized” enough to modify the disease process in PD patients. We also consider at what phases of the disease that such strategies might be effective, in light of the genes being primarily associated with the risk of developing disease in the first place, and less clearly linked to the rate of disease progression. Finally, we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider segment of PD patients, beyond those that actually carry risk variants of these genes.

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Leucine-rich repeat kinase-2 (LRRK2) modulates microglial phenotype and dopaminergic neurodegeneration

Cited by 36 publications

References 53 publications

Environmental toxicant exposure and Parkinson’s disease: LRRK2 and inflammatory processes

Environmental toxicant exposure and Parkinson’s disease: LRRK2 and inflammatory processes

Pathologic α-Synuclein Species Activate LRRK2 in Pro-Inflammatory Monocyte and Macrophage Responses

Precision medicine in Parkinson’s disease patients with LRRK2 and GBA risk variants – Let’s get even more personal

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