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

Wallings, Rebecca; Herrick, Mary K.; Tansey, Malú G.

doi:10.3389/fnins.2020.00443

Cited by 60 publications

(70 citation statements)

References 161 publications

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“…The current study adds further support to the hypothesis suggesting an involvement of the peripheral and central immune system in PD. On top of the HLA locus, several other genes with potential roles in the immune system, including LRRK2 and potentially BST1 , 8, 10 have been implicated in PD. 7 In the periphery, there are notable changes in the immune system of PD patients compared to controls, as peripheral monocytes have differential expression of immune related proteins and markers.…”

Section: Discussionmentioning

confidence: 99%

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Fine mapping of the HLA locus in Parkinson’s disease in Europeans

Ambati

Andersen

et al. 2020

Preprint

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Objective: Previous studies suggested a role for the immune system in Parkinson disease (PD), and one of the hits in recent genome-wide association studies (GWASs) of PD is within the human leukocyte antigen (HLA) locus. Several associations of different HLA genes have been suggested, yet it is not clear which associations are relevant for PD. Methods: We performed a thorough analysis of the HLA locus in 13,770 PD patients, 20,214 proxy-cases and 490,861 controls of European origin. We used GWAS data to impute HLA types and performed multiple regression models to examine the association of specific HLA types, different haplotypes and specific amino acid changes. We further performed conditional analyses to identify specific alleles or genetic variants that drive the association with PD. Results: Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1*03:01, HLA-DQB1*03:02, HLA-DRB1*04:01 and HLA-DRB1*04:04. Haplotype analyses followed by amino-acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1*04 subtypes - 11V, 13H and 33H (OR=0.87 95%CI=0.83-0.90, p<8.23x10-9 for all three variants). No other effects were present after adjustment for these amino acids. Interpretation: Our results suggest that specific variants in the HLA-DRB1 gene are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to identification of new targets for therapeutics development.

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Section: Discussionmentioning

confidence: 99%

“…4, 5 Genetic evidence also links the immune system with PD, since genes such as LRRK2 , the HLA locus and possibly BST1 , all associated with PD 7 and have a role in the immune system. 8-10…”

Section: Introductionmentioning

confidence: 99%

Fine mapping of the HLA locus in Parkinson’s disease in Europeans

Ambati

Andersen

et al. 2020

Preprint

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“…Mutations in LRRK2 ( PARK8 ) gene are the most common genetic cause of both familial and sporadic PD [ 132 ]. Besides PD, mutations in the LRRK2 gene are also found in immune-related disorders, such as inflammatory bowel disease (IBD) and some bacterial infections [ 133 ]. In a genome-wide association study, it was also reported that LRRK2 mutations are associated with autoimmune diseases such as type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis [ 134 ].…”

Section: Genomics Of Pd-related Inflammationmentioning

confidence: 99%

“…Therefore, LRRK2 seems to participate in the regulation of inflammatory responses not only in the brain but also at a systemic level. In fact, LRRK2 expression is expressed in microglia but also in peripheral immune cells such as monocytes, neutrophils, dendritic cells and, to a lower extent, in B and T cells [ 133 , 135 ]. LRRK2 modulates several pathways in innate and adaptive immunity by interfering with NF-κB and NF-AT signaling [ 136 ].…”

Section: Genomics Of Pd-related Inflammationmentioning

confidence: 99%

Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

Pajares

Rojo

Manda

et al. 2020

Cells

481

296

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Parkinson’s disease (PD) is a common neurodegenerative disorder primarily characterized by the death of dopaminergic neurons that project from the substantia nigra pars compacta. Although the molecular bases for PD development are still little defined, extensive evidence from human samples and animal models support the involvement of inflammation in onset or progression. However, the exact trigger for this response remains unclear. Here, we provide a systematic review of the cellular mediators, i.e., microglia, astroglia and endothelial cells. We also discuss the genetic and transcriptional control of inflammation in PD and the immunomodulatory role of dopamine and reactive oxygen species. Finally, we summarize the preclinical and clinical approaches targeting neuroinflammation in PD.

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“…49 Inflammatory cytokine secretion from monocytes is greater in iPD patients than in controls and correlates with LRRK2 expression in T cells in iPD patients (but not controls). 49 These findings suggest that the function of LRRK2 in immune cells is altered in iPD and should be considered in research regarding the role of LRRK2 in iPD pathogenesis (reviewed in Wallings et al 51 ). Furthermore, when assessing therapies to target LRRK2, it is important to consider that the function of LRRK2 is highly cell-type-dependent and poorly understood.…”

Section: Lrrk2mentioning

confidence: 99%

Genetic and Environmental Factors in Parkinson's Disease Converge on Immune Function and Inflammation

et al. 2020

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A BS TRACT: Idiopathic Parkinson's disease (iPD) is a movement disorder characterized by the degeneration of dopaminergic neurons and aggregation of the protein α-synuclein. Patients with iPD vary in age of symptom onset, rate of progression, severity of motor and nonmotor symptoms, and extent of central and peripheral inflammation. Genetic and environmental factors are believed to act synergistically in iPD pathogenesis. We propose that environmental factors (pesticides and infections) increase the risk for iPD via the immune system and that the role of PD risk genes in immune cells is worthy of investigation. This review highlights the major PD-relevant genes expressed in immune cells and key environmental factors that activate immune cells and, alone or in combination with other factors, may contribute to iPD pathogenesis. By reviewing these interactions, we seek to enable the future development of immunomodulatory approaches to prevent or delay onset of iPD.

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

Cited by 60 publications

References 161 publications

Fine mapping of the HLA locus in Parkinson’s disease in Europeans

Fine mapping of the HLA locus in Parkinson’s disease in Europeans

Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

Genetic and Environmental Factors in Parkinson's Disease Converge on Immune Function and Inflammation

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