Abstract
BackgroundThere is evidence for a relevant role of inflammation in the pathogenesis of Parkinson’s disease (PD). Mutations in the LRRK2 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and LRRK2-associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting LRRK2 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients.MethodsWe assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF LRRK2 consortium.ResultsA large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not LRRK2-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting LRRK2 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles.ConclusionsConcomitant inflammation seems to be associated with idiopathic and LRRK2-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting LRRK2 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0588-5) contains supplementary material, which is available to authorized users.
Highlights
There is evidence for a relevant role of inflammation in the pathogenesis of Parkinson’s disease (PD)
Clinical data and serum samples of 534 individuals from Canada, France, Germany, Norway, Spain, and the USA grouped into 4 cohorts were included in these cross-sectional analyses: (1) 144 idiopathic PD (IPD) patients controlled to have no pathogenic mutation in the leucine-rich repeat kinase (LRRK2) gene, (2) 142 Parkinson’s disease with LRRK2 mutation (PDLRRK2), (3) 115 NMCLRRK2, and (4) 133 healthy control individuals controlled to have no pathogenic LRRK2 mutation (CON); please see Additional file 1: Table S1 for the type of mutations and their distribution among the LRRK2 cohorts
IPD but not PDLRRK2 had significantly higher levels of the pro-inflammatory marker IL-12-p40 as well as of the anti-inflammatory marker IL-10, the neurotrophic factor brain-derived neurotrophic factor (BDNF), and the survival factor SCF compared to CON
Summary
There is evidence for a relevant role of inflammation in the pathogenesis of Parkinson’s disease (PD). Mutations in the LRRK2 gene represent the most frequent genetic cause for autosomal dominant PD. Mutations in the gene for leucine-rich repeat kinase (LRRK2) represent the most frequent genetic cause associated with autosomal dominant PD. LRRK2 is highly expressed in monocytes, macrophages, and microglia, and exposure to bacterial lipopolysaccharides (LPS) results in an up-regulation of LRRK2 protein as well as impaired autophagy in macrophages [4, 12]. Following this line, one could speculate that PDLRRK2 might be associated with distinct inflammatory cascades
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