Mutant LRRK2 in lymphocytes regulates neurodegeneration via IL-6 in an inflammatory model of Parkinson’s disease

Козина, Е. А.; Byrne, Matthew; Smeyne, Richard J.

doi:10.1038/s41531-022-00289-9

Cited by 19 publications

(23 citation statements)

References 111 publications

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“…In situ hybridization in mice demonstrated that it is highly expressed in the basal ganglia region associated with motor function in PD and non-motor regions, for example, the hippocampus [ 20 , 25 , 29 ]. LRRK2 was also found in high concentrations in leukocytes, such as monocytes, B lymphocytes, and dendritic cells [ 30 , 31 , 32 ]. Inside the cell, LRRK2 is mainly present in the cytoplasm, where it interacts with the 14-3-3 adaptor protein in a phosphorylation-dependent way [ 33 , 34 ].…”

Section: Lrrk2 and Its Functionmentioning

confidence: 99%

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Thakur

Kumar

Lee

et al. 2022

Genes

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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, characterized by the specific loss of dopaminergic neurons in the midbrain. The pathophysiology of PD is likely caused by a variety of environmental and hereditary factors. Many single-gene mutations have been linked to this disease, but a significant number of studies indicate that mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a potential therapeutic target for both sporadic and familial forms of PD. Consequently, the identification of potential LRRK2 inhibitors has been the focus of drug discovery. Various investigations have been conducted in academic and industrial organizations to investigate the mechanism of LRRK2 in PD and further develop its inhibitors. This review summarizes the role of LRRK2 in PD and its structural details, especially the kinase domain. Furthermore, we reviewed in vitro and in vivo findings of selected inhibitors reported to date against wild-type and mutant versions of the LRRK2 kinase domain as well as the current trends researchers are employing in the development of LRRK2 inhibitors.

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Section: Lrrk2 and Its Functionmentioning

confidence: 99%

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Thakur

Kumar

Lee

et al. 2022

Genes

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“…As B cells can actively express LRRK2, these processes may play an essential role in B cell-mediated DA neuronal apoptosis. As expected, follow-up studies found that LRRK2 mutations in B cells aggravated LPS-mediated neuroinflammation and accelerated DA neuronal loss in the SN [ 58 ]. In addition, LRRK2 and CD38 were found to exist in the plasma membrane complex in B cells and act as upstream regulatory molecules of host defence transcription factor TFEB (transcription factor EB) to affect autophagy, which plays a potential role in promoting DA neuron apoptosis [ 59 ].…”

Section: Autoimmune Cells In the Pathogenesis Of Da Neuron Apoptosis ...mentioning

confidence: 59%

Mechanisms of Autoimmune Cell in DA Neuron Apoptosis of Parkinson’s Disease: Recent Advancement

Zheng

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that manifests as motor and nonmotor symptoms due to the selective loss of midbrain DArgic (DA) neurons. More and more studies have shown that pathological reactions initiated by autoimmune cells play an essential role in the progression of PD. Autoimmune cells exist in the brain parenchyma, cerebrospinal fluid, and meninges; they are considered inducers of neuroinflammation and regulate the immune in the human brain in PD. For example, T cells can recognize α-synuclein presented by antigen-presenting cells to promote neuroinflammation. In addition, B cells will accelerate the apoptosis of DA neurons in the case of PD-related gene mutations. Activation of microglia and damage of DA neurons even form the self-degeneration cycle to deteriorate PD. Numerous autoimmune cells have been considered regulators of apoptosis, α-synuclein misfolding and aggregation, mitochondrial dysfunction, autophagy, and neuroinflammation of DA neurons in PD. The evidence is mounting that autoimmune cells promote DA neuron apoptosis. In this review, we discuss the current knowledge regarding the regulation and function of B cell, T cell, and microglia as well as NK cell in PD pathogenesis, focusing on DA neuron apoptosis to understand the disease better and propose potential target identification for the treatment in the early stages of PD. However, there are still some limitations in our work, for example, the specific mechanism of PD progression caused by autoimmune cells in mitochondrial dysfunction, ferroptosis, and autophagy has not been clarified in detail, which needs to be summarized in further work.

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“…In addition, it is unknown whether cohesion defects as determined in the blood are mirrored by centrosomal/ciliary defects in the brain (40,44), and evidence for LRRK2 kinase-mediated ciliary defects in the human brain is currently lacking. It is also unknown whether the cohesion defects observed in lymphocytes trigger peripheral immune responses which then initiate a neurodegenerative cascade (81), possibly in the In sum, we here provide evidence that cohesion deficits are present in primary lymphocytes from LRRK2 PD patients and non-manifesting LRRK2 mutation carriers. They are also observed in a subset of early-stage idiopathic PD patients and are sensitive to LRRK2 kinase treatment.…”

Section: Discussionmentioning

confidence: 73%

A potential patient stratification biomarker for Parkinso’s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells

Naaldijk

Fernández

Fasiczka

et al. 2023

Preprint

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Parkinson's disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they acumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate PD patients who will benefit from LRRK2-related therapeutics.

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Mutant LRRK2 in lymphocytes regulates neurodegeneration via IL-6 in an inflammatory model of Parkinson’s disease

Cited by 19 publications

References 111 publications

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Mechanisms of Autoimmune Cell in DA Neuron Apoptosis of Parkinson’s Disease: Recent Advancement

A potential patient stratification biomarker for Parkinso’s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells

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