Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Wallings RL

PROVIDER: S-EPMC7253584 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Wallings Rebecca L RL Herrick Mary K MK Tansey Malú Gámez MG

Frontiers in neuroscience 20200521

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 tube ...[more]

PMID: 32508566

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Project description:Most neurodegenerative disorders take decades to develop, and their early detection is challenged by confounding non-pathological ageing processes. Therefore, the discovery of genes and molecular pathways in both peripheral and brain tissues that are highly predictive of disease evolution is necessary. To find genes that influence Alzheimer's disease (AD) and Parkinson's disease (PD) pathogenesis, human RNA-Seq transcriptomic data from Brodmann Area 9 (BA9) of the dorsolateral prefrontal cortex (DLPFC), whole blood (WB), and peripheral blood mononuclear cells (PBMC) were analysed using a combination of differential gene expression and a random forest-based machine learning algorithm. The results suggest that there is little overlap between PD and AD, and the AD brain signature is unique mainly compared to blood-based samples. Moreover, the AD-BA9 was characterised by changes in 'nervous system development' with Myocyte-specific enhancer factor 2C (Mef2C), encoding a transcription factor that induces microglia activation, a prominent feature. The peripheral AD transcriptome was associated with alterations in 'viral process', and FYN, which has been previously shown to link amyloid-beta and tau, was the prominent feature. However, in the absence of any overlap with the central transcriptome, it is unclear whether peripheral FYN levels reflect AD severity or progression. In PD, central and peripheral signatures are characterised by anomalies in 'exocytosis' and specific genes related to the SNARE complex, including Vesicle-associated membrane protein 2 (VAMP2), Syntaxin 1A (STX1A), and p21-activated kinase 1 (PAK1). This is consistent with our current understanding of the physiological role of alpha-synuclein and how alpha-synuclein oligomers compromise vesicle docking and neurotransmission. Overall, the results describe distinct disease-specific pathomechanisms, both within the brain and peripherally, for the two most common neurodegenerative disorders.

Project description:Mutations associated with leucine-rich repeat kinase 2 are the most common known cause of Parkinson's disease. The known expression of leucine-rich repeat kinase 2 in immune cells and its negative regulatory function of nuclear factor of activated T cells implicates leucine-rich repeat kinase 2 in the development of the inflammatory environment characteristic of Parkinson's disease. The aim of this study was to determine the expression pattern of leucine-rich repeat kinase 2 in immune cell subsets and correlate it with the immunophenotype of cells from Parkinson's disease and healthy subjects. For immunophenotyping, blood cells from 40 Parkinson's disease patients and 32 age and environment matched-healthy control subjects were analyzed by flow cytometry. Multiplexed immunoassays were used to measure cytokine output of stimulated cells. Leucine-rich repeat kinase 2 expression was increased in B cells (p = 0.0095), T cells (p = 0.029), and CD16+ monocytes (p = 0.01) of Parkinson's disease patients compared to healthy controls. Leucine-rich repeat kinase 2 induction was also increased in monocytes and dividing T cells in Parkinson's disease patients compared to healthy controls. In addition, Parkinson's disease patient monocytes secreted more inflammatory cytokines compared to healthy control, and cytokine expression positively correlated with leucine-rich repeat kinase 2 expression in T cells from Parkinson's disease but not healthy controls. Finally, the regulatory surface protein that limits T-cell activation signals, CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), was decreased in Parkinson's disease compared to HC in T cells (p = 0.029). In sum, these findings suggest that leucine-rich repeat kinase 2 has a regulatory role in immune cells and Parkinson's disease. Functionally, the positive correlations between leucine-rich repeat kinase 2 expression levels in T-cell subsets, cytokine expression and secretion, and T-cell activation states suggest that targeting leucine-rich repeat kinase 2 with therapeutic interventions could have direct effects on immune cell function.

Dataset Information

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

Publications

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

Similar Datasets

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