The Role of Innate and Adaptive Immunity in Parkinson's Disease

Kannarkat, George T.; Boss, Jeremy M.; Tansey, Malú G.

doi:10.3233/jpd-130250

Cited by 278 publications

(215 citation statements)

References 191 publications

(223 reference statements)

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“…FcεRI is the high-affinity receptor for Immunoglobulin E and is the major controller of the allergic response and associated inflammation. In general, immune-related inflammation has been frequently associated with Parkinson’s disease and several immuno-modulating therapies have been pursued, but it remains unclear whether this is a causal driver of the disease or is rather a result of the neurodegeneration associated with disease progression 56,57 . There has been relatively little focus on the specific role of FcεRI in Parkinson’s, but recent observations support the relevance of this pathway to the disease 58 .…”

Section: Resultsmentioning

confidence: 99%

Discovering genetic interactions bridging pathways in genome-wide association studies

Fang

Wang

Paunić

et al. 2017

Preprint

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Genetic interactions have been reported to underlie phenotypes in a variety of systems, but the extent to which they contribute to complex disease in humans remains unclear. In principle, genome-wide association studies (GWAS) provide a platform for detecting genetic interactions, but existing methods for identifying them from GWAS data tend to focus on testing individual locus pairs, which undermines statistical power. Importantly, the global genetic networks mapped for a model eukaryotic organism revealed that genetic interactions often connect genes between compensatory functional modules in a highly coherent manner. Taking advantage of this expected structure, we developed a computational approach called BridGE that identifies pathways connected by genetic interactions from GWAS data.Applying BridGE broadly, we discovered significant interactions in Parkinson's disease, schizophrenia, hypertension, prostate cancer, breast cancer, and type 2 diabetes. Our novel approach provides a general framework for mapping complex genetic networks underlying human disease from genome-wide genotype data.. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/182741 doi: bioRxiv preprint first posted online Aug. 30, 2017; 3 Genome-wide association studies (GWAS) have been increasingly successful at identifying single-nucleotide polymorphisms (SNPs) with statistically significant association to a variety of diseases [1][2][3][4][5] and gene sets significantly enriched for SNPs with moderate association [6][7][8][9][10] . However, for most diseases, there remains a substantial disparity between the disease risk explained by the discovered loci and the estimated total heritable disease risk based on familial aggregation [11][12][13][14][15][16] . While there are a number of possible explanations for this "missing heritability", including many loci with small effects or rare variants [11][12][13][14][15]17 , genetic interactions between loci are one potential culprit 13,14,16,18,19 . Genetic interactions generally refer to a combination of two or more genes whose contribution to a phenotype cannot be completely explained by their independent effects 16,20,21 , For example, one example of an extreme genetic interaction is synthetic lethality, which is the case where two mutations, neither of which is lethal on its own, combines to generate a lethal double mutant phenotype. Genetic interactions allow relatively benign variation to combine and generate more extreme phenotypes, including complex human diseases [11][12][13]16,22 .While several studies have reported interactions between genetic variants in various disease contexts 20,[23][24][25][26] , and though efficient and scalable computational tools have been developed for searching for interactions amongst genome wide SNPs 20,[26][27][28] , discovering them systematically with statistical significance remains a major challenge. For examp...

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Section: Resultsmentioning

confidence: 99%

Discovering genetic interactions bridging pathways in genome-wide association studies

Fang

Wang

Paunić

et al. 2017

Preprint

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“…Indeed, co-morbidity between Parkinson’s disease and Crohn’s disease indicates that people diagnosed with PD could suffer from this dysregulation within the periphery, evidence for the potential involvement of the immune system as a player in vulnerability of PD, as well (Nalls et al, 2014). A recent review assesses the role of monocytes of the innate immune system in PD, including the promotion of neuroinflammation and the infiltration of peripheral macrophages, and supports a hypothesis of broad monocyte dysfunction in PD (Kannarkat et al, 2013). Thus, the etiology of PD could be partially rooted in an improper reactivity of monocytes such as microglia in response to native stimuli, including the protein αSyn, a central player in the pathogenesis and neuropathology of PD.…”

Section: Influence Of Autophagy In the Immune Systemmentioning

confidence: 87%

The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson’s disease

2015

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The proteins alpha-synuclein (αSyn) and LRRK2 are both key players in the pathogenesis of the neurodegenerative disorder Parkinson’s disease (PD), but establishing a functional link between the two proteins has proven elusive. Research studies for these two proteins have traditionally and justifiably focused in neuronal cells, but recent studies indicate that each protein could play a greater pathological role elsewhere. αSyn is expressed at high levels within neurons, but they also secrete the protein into the extracellular milieu, where it can have broad ranging effects in the nervous system and relevance to disease etiology. Similarly, low neuronal LRRK2 expression and activity suggests that LRRK2-related functions could be more relevant in cells with higher expression, such as brain-resident microglia. Microglia are monocytic immune cells that protect neurons from noxious stimuli, including pathological αSyn species, and microglial activation is believed to contribute to neuroinflammation and neuronal death in PD. Interestingly, both αSyn and LRRK2 can be linked to microglial function. Secreted αSyn can directly activate microglia, and can be taken up by microglia for clearance, while LRRK2 has been implicated in the intrinsic regulation of microglial activation and of lysosomal degradation processes. Based on these observations, the present review will focus on how PD-associated mutations in LRRK2 could potentially alter microglial biology with respect to neuronally-secreted αSyn, resulting in cell dysfunction and neurodegeneration.

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“…6 Yet, it is debated whether the altered immune responses play a causal role or are purely secondary to the neuronal damages in these diseases. 26,27 In contrast to the proposed pathophysiological similarities, it is interesting to note that ALS and PD do appear to have different risk factors. For example, smoking has been repeatedly shown as a protective factor for PD, 17 but has been recently suggested to be causally related to a higher risk of ALS.…”

Section: Discussionmentioning

confidence: 99%

Peripheral immune biomarkers and neurodegenerative diseases: A prospective cohort study with 20 years of follow‐up

Yazdani

Mariosa

Hammar

et al. 2019

Annals of Neurology

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Objective To assess the associations of several blood immune biomarkers with the future risks of amyotrophic lateral sclerosis and Parkinson disease in a prospective cohort study with 20 years of follow‐up. Methods The Swedish Apolipoprotein‐Related Mortality Risk study is a longitudinal cohort study including 812,073 participants with repeated blood biomarker measurements between 1985 and 1996 and a follow‐up until 2011. Using a Cox model, we first estimated hazard ratios of amyotrophic lateral sclerosis and Parkinson disease in relation to leukocytes, immunoglobulin G, haptoglobin, and uric acid. We further described the temporal changes of these biomarkers during the 20 years prior to the diagnosis of these diseases. Results A total of 585 incident cases of amyotrophic lateral sclerosis and 3,769 incident cases of Parkinson disease were identified during the follow‐up. Increasing concentrations of leukocytes, haptoglobin, and uric acid were associated with a lower risk of Parkinson disease. No statistically significant association was, however, noted between the studied biomarkers and amyotrophic lateral sclerosis. Parkinson disease patients appeared to have lower levels of leukocytes and haptoglobin between 20 and 10 years before diagnosis and lower levels of uric acid during the 20 years before diagnosis, compared to controls, although statistically significant differences were only noted during parts of the respective time intervals after multivariable adjustment. No clear differences were noted between patients with amyotrophic lateral sclerosis and controls. Interpretation If verified in studies of independent populations, our findings may suggest a different role of systemic inflammation on the risk of Parkinson disease compared to amyotrophic lateral sclerosis. ANN NEUROL 2019;86:913–926

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The Role of Innate and Adaptive Immunity in Parkinson's Disease

Cited by 278 publications

References 191 publications

Discovering genetic interactions bridging pathways in genome-wide association studies

Discovering genetic interactions bridging pathways in genome-wide association studies

The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson’s disease

Peripheral immune biomarkers and neurodegenerative diseases: A prospective cohort study with 20 years of follow‐up

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