LRRK2 Kinase Activity Induces Mitochondrial Fission in Microglia via Drp1 and Modulates Neuroinflammation

Ho, Dong Hwan; Je, A Reum; Lee, Hae-Jin; Son, Ilhong; Kweon, Hee‐Seok; Kim, Hyunggun; Seol, Wongi

doi:10.5607/en.2018.27.3.171

Cited by 72 publications

(65 citation statements)

References 53 publications

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“…Previous studies of microglia have shown that LRRK2 contributes to mitochondrial homeostasis through interaction with the mitochondrial fission protein DRP1 (Ho et al, 2018). Thus, we hypothesized that the loss of Lrrk2 may compromise mitochondrial stability via misregulation of DRP1 activity, leading to fragmented mitochondria and spillage of mtDNA into the cytosol.…”

Section: Defects In Type I Ifn Responses In Lrrk2 Ko Macrophages Are mentioning

confidence: 95%

LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

Weindel

Bell

Vail

et al. 2020

eLife

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The Parkinson’s disease (PD)-associated gene leucine-rich repeat kinase 2 (LRRK2) has been studied extensively in the brain. However, several studies have established that mutations in LRRK2 confer susceptibility to mycobacterial infection, suggesting LRRK2 also controls immunity. We demonstrate that loss of LRRK2 in macrophages induces elevated basal levels of type I interferon (IFN) and interferon stimulated genes (ISGs) and causes blunted interferon responses to mycobacterial pathogens and cytosolic nucleic acid agonists. Altered innate immune gene expression in Lrrk2 knockout (KO) macrophages is driven by a combination of mitochondrial stresses, including oxidative stress from low levels of purine metabolites and DRP1-dependent mitochondrial fragmentation. Together, these defects promote mtDNA leakage into the cytosol and chronic cGAS engagement. While Lrrk2 KO mice can control Mycobacterium tuberculosis (Mtb) replication, they have exacerbated inflammation and lower ISG expression in the lungs. These results demonstrate previously unappreciated consequences of LRRK2-dependent mitochondrial defects in controlling innate immune outcomes.

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Section: Defects In Type I Ifn Responses In Lrrk2 Ko Macrophages Are mentioning

confidence: 95%

LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

Weindel

Bell

Vail

et al. 2020

eLife

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“…It has recently been suggested that LRRK2 may promote mitochondrial fission via Drp1 in a kinase-dependent manner, with increased fission due to G2019S-LRRK2 expression resulting in increased TNF-α production in the brains of mice (Ho et al, 2018). Brain lysates of G2019S-LRRK2 knock-in mice exhibited reduced NFkB p50 s337 phosphorylation, decreasing NFkB p50 inhibitory signaling and pro-inflammatory gene transcription, compared to WT mice (Russo et al, 2018).…”

Section: Lrrk2 Expression In Cells Of the Cns And Peripheral Immune Cmentioning

confidence: 99%

LRRK2 at the Interface Between Peripheral and Central Immune Function in Parkinson’s

2020

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It is becoming increasingly accepted that there is an interplay between the peripheral immune response and neuroinflammation in the pathophysiology of Parkinson's disease (PD). Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene are associated with familial and sporadic cases of PD but are also found in immune-related disorders, such as inflammatory bowel disease (IBD) and leprosy. Furthermore, LRRK2 has been associated with bacterial infections such as Mycobacterium tuberculosis and Salmonella typhimurium. Recent evidence suggests a role of LRRK2 in the regulation of the immune system and modulation of inflammatory responses, at a systemic level, with LRRK2 functionally implicated in both the immune system of the central nervous system (CNS) and the periphery. It has therefore been suggested that peripheral immune signaling may play an important role in the regulation of neurodegeneration in LRRK2 as well as non-LRRK2-associated PD. This review will discuss the current evidence for this hypothesis and will provide compelling rationale for placing LRRK2 at the interface between peripheral immune responses and neuroinflammation.

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“…6.2.1 | Drp1 involve in the mutant leucine rich-repeat kinase 2 (LRRK2)-induced PD LRRK2, a pathogenic gene of PD, has many functions including regulating the transportation of vesicles, the autophagy, oxidative stress, neurotoxicity, and mitochondrial dynamics. It is reported that 13% of familial PD patients and 1-2% of nonfamilial PD patients have mutations in the LRRK2 gene (Ho et al, 2018;Perez Carrion et al, 2018).…”

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confidence: 99%

Dynamin‐related protein 1: A critical protein in the pathogenesis of neural system dysfunctions and neurodegenerative diseases

Huang

Xie

et al. 2018

Journal Cellular Physiology

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Mitochondria play a key role in the maintenance of neuronal function by continuously providing energy. Here, we will give a detailed review about the recent developments in regards to dynamin‐related protein 1 (Drp1) induced unbalanced mitochondrial dynamics, excessive mitochondrial division, and neuronal injury in neural system dysfunctions and neurodegenerative diseases, including the Drp1 knockout induced mice embryonic death, the dysfunction of the Drp1‐dependent mitochondrial division induced neuronal cell apoptosis and impaired neuronal axonal transportation, the abnormal interaction between Drp1 and amyloid β (Aβ) in Alzheimer's disease (AD), the mutant Huntingtin (Htt) in Huntington's disease (HD), and the Drp1‐associated pathogenesis of other neurodegenerative diseases such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Drp1 is required for mitochondrial division determining the size, shape, distribution, and remodeling as well as maintaining of mitochondrial integrity in mammalian cells. In addition, increasing reports indicate that the Drp1 is involved in some cellular events of neuronal cells causing some neural system dysfunctions and neurodegenerative diseases, including impaired mitochondrial dynamics, apoptosis, and several posttranslational modification induced increased mitochondrial divisions. Recent studies also revealed that the Drp1 can interact with Aβ, phosphorylated τ, and mutant Htt affecting the mitochondrial shape, size, distribution, axonal transportation, and energy production in the AD and HD neuronal cells. These changes can affect the health of mitochondria and the function of synapses causing neuronal injury and eventually leading to the dysfunction of memory, cognitive impairment, resting tremor, posture instability, involuntary movements, and progressive muscle atrophy and paralysis in patients.

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LRRK2 Kinase Activity Induces Mitochondrial Fission in Microglia via Drp1 and Modulates Neuroinflammation

Cited by 72 publications

References 53 publications

LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

LRRK2 at the Interface Between Peripheral and Central Immune Function in Parkinson’s

Dynamin‐related protein 1: A critical protein in the pathogenesis of neural system dysfunctions and neurodegenerative diseases

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