Triggers, Facilitators, and Aggravators: Redefining Parkinson’s Disease Pathogenesis
Authors: Michaela E. Johnson, Benjamin Stecher, Viviane Labrie, Lena Brundin, Patrik Brundin
Journal: Trends in Neurosciences (2018)

We propose a new conceptual model for PD pathogenesis, in which disease-associated factors are divided into three categories: triggers, facilitators, and aggravators. Triggers are agents or events that begin the disease process; these factors are necessary but insufficient for PD to develop. Facilitators are factors that allow the disease to spread to, and significantly impact, the central nervous system. Aggravators directly promote the neurodegenerative process and often have a snowballing effect that exacerbates pathology and spreads the disease beyond the basal ganglia. We propose that clinical therapies aimed at slowing or arresting PD progression should not only be given to patients enriched for the appropriate target (i.e., administered to the appropriate subpopulation), but also be applied during the appropriate temporal phase at which the relevant factor is most active. We hypothesize that Parkinson's disease (PD) pathogenesis can be divided into three temporal phases. During the first phase, 'triggers', such as viral infections or environmental toxins, spark the disease process in the brain and/or peripheral tissues. Triggers alone, however, may be insufficient, requiring 'facilitators' like peripheral inflammation for PD pathology to develop. Once the disease manifests, 'aggravators' spur further neurodegeneration and exacerbate symptoms. Aggravators are proposed to include impaired autophagy and cell-to-cell propagation of α-synuclein pathology. We believe clinical trials need to consider these three phases and target potential therapies at the appropriate stage of the disease process in order to be effective. We hypothesize that Parkinson's disease (PD) pathogenesis can be divided into three temporal phases. During the first phase, 'triggers', such as viral infections or environmental toxins, spark the disease process in the brain and/or peripheral tissues. Triggers alone, however, may be insufficient, requiring 'facilitators' like peripheral inflammation for PD pathology to develop. Once the disease manifests, 'aggravators' spur further neurodegeneration and exacerbate symptoms. Aggravators are proposed to include impaired autophagy and cell-to-cell propagation of α-synuclein pathology. We believe clinical trials need to consider these three phases and target potential therapies at the appropriate stage of the disease process in order to be effective. A crucial unmet need for patients with Parkinson's disease (PD) is a disease-modifying therapy. This is particularly urgent considering that the number of people with PD is set to double over the next 20 years, with over 14 million PD cases expected worldwide by 2040 [1Dorsey E.R. Bloem B.R. The Parkinson pandemic — a call to action.JAMA Neurol. 2018; 75: 9-10Crossref PubMed Scopus (395) Google Scholar]. We believe that an inadequate understanding of the relative relationship and temporal sequence of factors involved in PD pathogenesis might be hampering advances of new therapies. Many past attempts to develop therapies were designed with the aim of slowing disease progression by targeting single molecular pathways in PD pathogenesis; these attempts also typically viewed PD as a uniform disease, and subsequently treated all patients with the same therapeutic regimen. The PD research field is now questioning the accuracy of considering PD as a single entity. Instead it has been suggested that PD is in fact an umbrella term given to a large cluster of disorders encompassing a range of clinical, epidemiological, molecular, neuropathological, and genetic subtypes [2Espay A.J. et al.Precision medicine for disease modification in Parkinson disease.Nat. Rev. Neurol. 2017; 13: 119Crossref PubMed Scopus (94) Google Scholar, 3Espay A.J. et al.Biomarker-driven phenotyping in Parkinson's disease: a translational missing link in disease-modifying clinical trials.Mov. Disord. 2017; 32: 319-324Crossref PubMed Scopus (97) Google Scholar]. We would argue that if research programs culminate in clinical trials that continue to target a single pathogenic mechanism in groups of patients defined by the broad clinical diagnosis of PD, they are unlikely to yield effective disease-modifying treatment. We agree with the view that PD patients are a heterogenous population and, at best, patients can be grouped into different clusters with certain shared characteristics. In this opinion piece, we hypothesize that in a given patient, or patient cluster, the prevailing pathological mechanism will change during the different phases of PD. Based on this hypothesis, we propose a new conceptual model for PD pathogenesis. From the treatment perspective, the proposed model implies that medical interventions need to be disease-stage specific and personalized to maximize the chances of modifying the course of the disease. Specifically, our model first divides the factors that contribute to neurodegeneration into three categories: triggers, facilitators, and aggravators. Second, we argue that each of these factors play distinct roles at different stages of the disease. Triggers encompass factors that enable the initiation of the disease process. These are most prominent during the period of 'prodromal PD'. However, triggers alone are, in most cases, insufficient for PD to develop, as they require the presence of 'facilitators' for the disease to spread to, and significantly impact, the central nervous system. We propose that this applies not only to idiopathic PD, but also to familial forms of PD, as no known genetic form has complete penetrance, and the onset of PD symptoms in the familial forms are known to occur over a wide age span. We acknowledge that familial cases have a greater contribution of genetic factors as a facilitator event, compared with idiopathic PD. Facilitators can also be factors that sensitize cells to the toxic effects of triggers and promote a neurodegenerative cascade that may involve the formation and/or seeding of pathogenic α-synuclein. It would be necessary for these facilitators to be present during the initial stages of the disease process, when α-synuclein pathology transitions to the midbrain after initially being confined to a small number of cells in peripheral locations in the nervous system (e.g., enteric nerves) or central ones (e.g., olfactory system). Finally, we suggest a third category of factors that contribute to PD pathogenesis. These are 'aggravators', which directly promote the neurodegenerative process by exacerbating the pathology and promoting the spread of the disease beyond the basal ganglia. The phases where triggers, facilitators, and aggravators act do not necessarily have distinct boundaries; rather, they represent a continuum along the disease course. The proposed terminology, however, can be helpful as a conceptual framework for articulating more clearly when, across a process that typically lasts several decades, different factors act, and what are their key roles. We think our hypothesized framework will facilitate the development of selective therapies that target the right mechanism at the right time. We will use examples to illustrate how key biological mediators of PD pathophysiology can be divided into the three categories of triggers, facilitators, and aggravators (Figure 1), and we will examine when is it during the disease process that they are most likely to play a critical role in PD pathogenesis. With the exception of relatively rare genetic forms of PD, triggers of PD are largely unknown. Yet a number of suspected triggers have been inferred from endogenous functions of candidate PD risk genes, and from findings in experimental animals. In idiopathic PD, the triggers are thought to act decades before the loss of nigrostriatal dopaminergic signaling has reached levels necessary for the onset of clinical motor symptoms [4Ross G.W. et al.Parkinsonian signs and substantia nigra neuron density in decendents elders without PD.Ann. Neurol. 2004; 56: 532-539Crossref PubMed Scopus (191) Google Scholar, 5Marsden C.D. Parkinson's disease.Lancet. 1990; 335: 948-952Abstract PubMed Scopus (0) Google Scholar]. We propose that triggers often act transiently, with the triggering event lasting a few weeks or months and occurring relatively early in the life of individuals that will develop PD. The transient nature of such triggers makes them particularly difficult to detect, and a thorough review of patient medical histories may be necessary to identify possible triggers. Several triggers of PD have already been proposed and include pathogens and environmental toxins, as well as head trauma (Table 1). Potential outcomes of triggering events may include long-term gut dysfunction [6Barreau F. Hugot J. Intestinal barrier dysfunction triggered by invasive bacteria.Curr. Opin. Microbiol. 2014; 17: 91-98Crossref PubMed Scopus (77) Google Scholar], chronic inflammation in critical tissues [7da Fonseca D.M. et al.Microbiota-dependent sequelae of acute infection compromise tissue-specific immunity.Cell. 2015; 163: 354-366Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar], or the direct misfolding of α-synuclein into pathogenic conformers (e.g., resulting from exposure to heavy metals) [8Uversky V.N. et al.Metal-triggered structural transformations, aggregation, and fibrillation of human α-synuclein a possible molecular link between Parkinson's disease and heavy metal exposure.J. Biol. Chem. 2001; 276: 44284-44296Crossref PubMed Scopus (926) Google Scholar]. Two anatomical sites have been suggested to be of particular relevance as places of origin for PD pathology. In 2003, Braak and colleagues first proposed that the olfactory epithelium and intestines might be where PD begins [9Braak H. et al.Staging of brain pathology related to sporadic Parkinson's disease.Neurobiol. Aging. 2003; 24: 197-211Abstract Full Text Full Text PDF PubMed Scopus (7188) Google Scholar]. This was based on the histological observation of α-synuclein aggregates in these sites in very early stage PD, and even in cases presumed to be prodromal PD [9Braak H. et al.Staging of brain pathology related to sporadic Parkinson's disease.Neurobiol. Aging. 2003; 24: 197-211Abstract Full Text Full Text PDF PubMed Scopus (7188) Google Scholar]. Gastrointestinal dysfunction and hyposmia are core features of PD, often occurring years to decades before the emergence of motor symptoms [10Schapira A.H. et al.Non-motor features of Parkinson disease.Nat. Rev. Neurosci. 2017; 18: 435-450Crossref PubMed Scopus (777) Google Scholar]. Their involvement in the early symptoms of PD, together with the findings of α-synuclein aggregates in these tissues [9Braak H. et al.Staging of brain pathology related to sporadic Parkinson's disease.Neurobiol. Aging. 2003; 24: 197-211Abstract Full Text Full Text PDF PubMed Scopus (7188) Google Scholar], indicate that the gastrointestinal tract and olfactory system might be trigger sites in PD pathogenesis. Below, we will use pathogens and microbiome changes, as well as pesticides and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as illustrative examples of potential triggers.Table 1Examples of Triggers Proposed to Spark the PD Pathogenic ProcessTriggersExamplesRefsGastrointestinal microbiota perturbationsIncreased LactobacillusReduced Prevotella21Sun M.F. Shen Y.Q. Dysbiosis of gut microbiota and microbial metabolites in Parkinson's disease.Ageing Res. Rev. 2018; 45: 53-61Crossref PubMed Scopus (191) Google Scholar21Sun M.F. Shen Y.Q. Dysbiosis of gut microbiota and microbial metabolites in Parkinson's disease.Ageing Res. Rev. 2018; 45: 53-61Crossref PubMed Scopus (191) Google ScholarPathogensHepatitis B and CNorovirusM. paratuberculosis75Kim J.M. et al.Association between hepatitis C virus infection and Parkinson's disease.Mov. Disord. 2016; 31: 1584-1585Crossref PubMed Scopus (19) Google Scholar11Stolzenberg E. et al.A role for neuronal alpha-synuclein in gastrointestinal immunity.J. Innate Immun. 2017; 9: 456-463Crossref PubMed Scopus (168) Google Scholar53Dow C.T. M. paratuberculosis and Parkinson's disease–is this a trigger.Med. Hypotheses. 2014; 83: 709-712Abstract Full Text Full Text PDF PubMed Scopus (23) Google ScholarAir pollutionParticulate matterCarbon monoxide76Jayaraj R.L. et al.Outdoor ambient air pollution and neurodegenerative diseases: the neuroinflammation hypothesis.Curr. Environ. Health Rep. 2017; 4: 166-179Crossref PubMed Scopus (126) Google Scholar76Jayaraj R.L. et al.Outdoor ambient air pollution and neurodegenerative diseases: the neuroinflammation hypothesis.Curr. Environ. Health Rep. 2017; 4: 166-179Crossref PubMed Scopus (126) Google ScholarPesticidesRotenoneParaquat23Gunnarsson L.G. Bodin L. Parkinson's disease and occupational exposures: a systematic literature review and meta-analyses.Scand. J. Work Environ. Health. 2017; 43: 197-209Crossref PubMed Scopus (38) Google Scholar23Gunnarsson L.G. Bodin L. Parkinson's disease and occupational exposures: a systematic literature review and meta-analyses.Scand. J. Work Environ. Health. 2017; 43: 197-209Crossref PubMed Scopus (38) Google ScholarHeavy metalsIronCopperManganese77Dusek P. et al.The neurotoxicity of iron, copper and manganese in Parkinson's and Wilson's diseases.J. Trace Elem. Med. Biol. 2015; 31: 193-203Crossref PubMed Scopus (166) Google Scholar77Dusek P. et al.The neurotoxicity of iron, copper and manganese in Parkinson's and Wilson's diseases.J. Trace Elem. Med. Biol. 2015; 31: 193-203Crossref PubMed Scopus (166) Google Scholar77Dusek P. et al.The neurotoxicity of iron, copper and manganese in Parkinson's and Wilson's diseases.J. Trace Elem. Med. Biol. 2015; 31: 193-203Crossref PubMed Scopus (166) Google ScholarHead traumaTraumatic brain injury78Camacho-Soto A. et al.Traumatic brain injury in the prodromal period of Parkinson's disease: a large epidemiological study using medicare data.Ann. Neurol. 2017; 82: 744-754Crossref PubMed Scopus (33) Google Scholar Open table in a new tab A growing number of bacterial and viral pathogens have been associated with a higher risk for developing PD. Even common gastrointestinal infections, such as norovirus, induce upregulation of α-synuclein in the gastrointestinal tract, potentially in an effort to rally an immune response [11Stolzenberg E. et al.A role for neuronal alpha-synuclein in gastrointestinal immunity.J. Innate Immun. 2017; 9: 456-463Crossref PubMed Scopus (168) Google Scholar]. Aggregated α-synuclein is present in the enteric nervous system in PD patients [12Barrenschee M. et al.Distinct pattern of enteric phospho-alpha-synuclein aggregates and gene expression profiles in patients with Parkinson's disease.Acta Neuropathol. Commun. 2017; 5: 1Crossref PubMed Scopus (66) Google Scholar], but it has also more recently been shown to occur in healthy people, indicating that α-synuclein aggregates in the gut are not specific to PD [13Chung S.J. et al.Alpha-synuclein in gastric and colonic mucosa in Parkinson's disease: limited role as a biomarker.Mov. Disord. 2016; 31: 241-249Crossref PubMed Scopus (63) Google Scholar, 14Killinger B.A. et al.The vermiform appendix contributes to the development of Parkinson's disease.Sci. Transl. Med. 2018; (in press)Crossref PubMed Scopus (161) Google Scholar]. We propose that aggregation of α-synuclein in the gut is not necessarily abnormal per se, and is most often part of an appropriate, self-contained inflammatory response following infection. We speculate that what differentiates those who develop PD from those who do not might be the presence of facilitators (see later) that amplify the α-synuclein aggregates and allow for their spread along the vagus nerve, eventually causing seeding in the brainstem and Lewy pathology in the central nervous system. Several studies have reported changes in gut microbiota in PD, including increases in Lactobacillus, Akkermansia, and Bifidobacterium, and decreases in Prevotella, Blautia, and Faecalibacterium [15Scheperjans F. The prodromal microbiome.Mov. Disord. 2018; 33: 5-7Crossref PubMed Scopus (18) Google Scholar]. The majority of these studies suffer from the confounder that anti-parkinsonian medication might change the gut microbiome [16Bedarf J.R. et al.Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson's disease patients.Genome Med. 2017; 9: 39Crossref PubMed Scopus (310) Google Scholar]. However, unmedicated patients with rapid eye movement (REM) sleep behavior disorder who exhibit a high conversion rate to PD display similar changes in the gut microbiota [17Heintz-Buschart A. et al.The nasal and gut microbiome in Parkinson's disease and idiopathic rapid eye movement sleep behavior disorder.Mov. Disord. 2018; 33: 88-98Crossref PubMed Scopus (291) Google Scholar]. This supports the idea that microbiota alterations occur in prodromal and early PD. Moreover, α-synuclein-overexpressing mice exposed to the microbiota from PD patients display exacerbated motor dysfunction compared with those that received microbiota from healthy donors, supporting perturbation of gut microbiota as a potential PD trigger [18Sampson T.R. et al.Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease.Cell. 2016; 167: 1469-1480Abstract Full Text Full Text PDF PubMed Scopus (1794) Google Scholar]. While all of the aforementioned studies have focused on the gut microbiome, it is possible that analogous changes in the nasal microbiome trigger α-synuclein aggregation in the olfactory bulb. Though studies of the nasal microbiome in PD are yet to yield any convincing differences [17Heintz-Buschart A. et al.The nasal and gut microbiome in Parkinson's disease and idiopathic rapid eye movement sleep behavior disorder.Mov. Disord. 2018; 33: 88-98Crossref PubMed Scopus (291) Google Scholar, 19Pereira P.A. et al.Oral and nasal microbiota in Parkinson's disease.Parkinsonism Relat. Disord. 2017; 38: 61-67Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar], even if present, one should note that such suggested changes might only be present transiently during the prodrome. We speculate that a localized effect of altered microbiota causing inflammation leads to α-synuclein aggregation in enteric nerves or the olfactory system, with propagation of pathology to more central locations. Thus, gut dysbiosis and/or small intestinal bacterial overgrowth, along with increased intestinal permeability, can cause systemic inflammation, which could spread to the central nervous system through systemic circulation and several neural pathways [20Duerkop B.A. et al.Immune responses to the microbiota at the intestinal mucosal surface.Immunity. 2009; 31: 368-376Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar]. The downstream effects of gastrointestinal dysbiosis could be mediated by endogenous inflammatory factors or by metabolites directly produced by the gut bacteria [21Sun M.F. Shen Y.Q. Dysbiosis of gut microbiota and microbial metabolites in Parkinson's disease.Ageing Res. Rev. 2018; 45: 53-61Crossref PubMed Scopus (191) Google Scholar]. Metabolites secreted from gut bacteria that have been proposed to impact glial biology and neuroinflammation include short chain fatty acids and tryptophan metabolites [18Sampson T.R. et al.Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease.Cell. 2016; 167: 1469-1480Abstract Full Text Full Text PDF PubMed Scopus (1794) Google Scholar]. Microbiome metabolites have been shown to induce microglia activation and motor deficits in α-synuclein transgenic mice [18Sampson T.R. et al.Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease.Cell. 2016; 167: 1469-1480Abstract Full Text Full Text PDF PubMed Scopus (1794) Google Scholar]. Such metabolites may modify brain activities by regulating peripheral immune cell function and/or through activation of the vagal nerve either directly (e.g., evoke nerve responses) or indirectly (e.g., through enteroendocrine cell signaling) [22Bonaz B. et al.The vagus nerve at the interface of the microbiota-gut-brain axis.Front. Neurosci. 2018; 12: 49Crossref PubMed Scopus (480) Google Scholar]. Epidemiological studies have linked pesticide exposure with increased PD risk. A recent meta-analysis reported that exposure to several common pesticides is associated with ≥50% increased risk for developing PD [23Gunnarsson L.G. Bodin L. Parkinson's disease and occupational exposures: a systematic literature review and meta-analyses.Scand. J. Work Environ. Health. 2017; 43: 197-209Crossref PubMed Scopus (38) Google Scholar]. Furthermore, it is plausible that exposure to more than one pesticide confers an even greater risk compared with exposure to any individual chemical [24Wang A. et al.Parkinson's disease risk from ambient exposure to pesticides.Eur. J. Epidemiol. 2011; 26: 547-555Crossref PubMed Scopus (239) Google Scholar]. In principle, pesticides could trigger PD pathogenesis via several possible mechanisms, including inhibiting mitochondrial complex I, inducing oxidative stress, stimulating inflammation, and causing α-synuclein fibrillization [25Baltazar M.T. et al.Pesticides exposure as etiological factors of Parkinson's disease and other neurodegenerative diseases—a mechanistic approach.Toxicol. Lett. 2014; 230: 85-103Crossref PubMed Scopus (256) Google Scholar]. Human dopaminergic neurons carrying the SNCA-A53T mutation develop impaired anterograde mitochondrial transport when exposed to regulated and approved pesticides [26Stykel M.G. et al.Nitration of microtubules blocks axonal mitochondrial transport in a human pluripotent stem cell model of Parkinson's disease.FASEB J. 2018; 32: 5350-5364Crossref PubMed Scopus (27) Google Scholar]. Exposure at these low levels caused impairment only in neurons carrying the PD mutation, supporting our concept that triggers (e.g., pesticides) need to be accompanied by a facilitator (e.g., PD risk mutation) to render neurons vulnerable to disease. Intravenous injection of the neurotoxin MPTP (e.g., through use of the synthetic analgesic drug MPPP when accidentally contaminated with MPTP) causes rapid death of nigral dopamine neurons and, consequently, PD symptoms [27Langston J.W. et al.Chronic parkinsonism in humans due to a product of meperidine-analog synthesis.Science. 1983; 219: 979-980Crossref PubMed Scopus (3954) Google Scholar]. However, the very acute nature of MPTP-induced parkinsonism limits its relevance to understanding familial or idiopathic PD. Furthermore, in the few individuals who injected MPTP intravenously and developed PD symptoms, the dose of the trigger (MPTP) was presumably so large that it overrode the need for a facilitator. Notably, not all people who injected MPTP developed parkinsonism and over 30 years ago, four cases exposed to MPTP intravenously were found to have reduced 6-fluorodopa uptake on positron emission scans, but no clinical signs of PD [28Calne D. et al.Positron emission tomography after MPTP: observations relating to the cause of Parkinson's disease.Nature. 1985; 317: 246Crossref PubMed Scopus (268) Google Scholar]. This suggests that the trigger in this case (MPTP) does not always cause significant nigral neurodegeneration, possibly due to the absence of appropriate facilitators or to a lower dose being injected. While MPTP-induced parkinsonism might be illustrative of the interrelationship between a trigger and its facilitators, the relevance to aggravators in idiopathic PD is probably limited because MPTP toxicity does not induce pathological hallmarks of PD-like Lewy bodies [29Masilamoni G.J. Smith Y. Chronic MPTP administration regimen in monkeys: a model of dopaminergic and non-dopaminergic cell loss in Parkinson's disease.J. Neural Transm. 2018; 125: 337-363Crossref PubMed Scopus (40) Google Scholar]. We define facilitators as factors that help triggers access the nervous system or spread the pathology to more central parts of the nervous system. We propose that the facilitator role in disease pathogenesis takes place concomitantly with the triggering event or after it, usually during the prodromal or asymptomatic phase of PD. Notably, facilitators and aggravators can either be permanent (e.g., in the form of a genetic predisposition) or transient, such as in the case of temporary gastrointestinal inflammation. PD development may depend on the simultaneous or proximal occurrence of the trigger and the facilitator; however, it is also conceivable that a trigger precedes the actions of a facilitator by several years. For example, pathogen-induced (trigger) inflammation in the gut resulting in localized α-synuclein accumulation and aggregation in enteric nerves [11Stolzenberg E. et al.A role for neuronal alpha-synuclein in gastrointestinal immunity.J. Innate Immun. 2017; 9: 456-463Crossref PubMed Scopus (168) Google Scholar] may not promote PD until years later, after an age-related decline in cellular energy homeostasis and lysosomal function (facilitators) has set in, which in turn could enable the propagation of α-synuclein aggregates to the brainstem. Inflammation in PD is present both in the periphery (systemic inflammation) and in the central nervous system [30Macchi B. et al.Inflammatory and cell death pathways in brain and peripheral blood in Parkinson's disease.CNS Neurol. Disord. Drug Targets. 2015; 14: 313-324Crossref PubMed Scopus (69) Google Scholar]. Genome-wide studies further revealed several polymorphisms in inflammatory genes associated with PD [31Hamza T.H. et al.Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease.Nat. Genet. 2010; 42: 781Crossref PubMed Scopus (592) Google Scholar, 32Chang D. et al.A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci.Nat. Genet. 2017; 49: 1511Crossref PubMed Scopus (633) Google Scholar, 33Pierce S. Coetzee G.A. Parkinson's disease-associated genetic variation is linked to quantitative expression of inflammatory genes.PLoS One. 2017; 12e0175882Crossref PubMed Scopus (33) Google Scholar]. At the molecular level, inflammatory mediators are known to promote α-synuclein misfolding and aggregation [34Gao H.-M. et al.Neuroinflammation and oxidation/nitration of α-synuclein linked to dopaminergic neurodegeneration.J. Neurosci. 2008; 28: 7687-7698Crossref PubMed Scopus (336) Google Scholar]. Importantly, there are also emerging, compelling links between inflammation and the spread of α-synuclein pathology, which could explain how systemic inflammation facilitates the propagation of α-synuclein pathology from peripheral tissues to the central nervous system [35Tyson T. et al.Sorting out release, uptake and processing of alpha-synuclein during prion-like spread of pathology.J. Neurochem. 2016; 139: 275-289Crossref PubMed Scopus (63) Google Scholar]. Notably, colon biopsies from PD patients exhibit increased mRNA levels for proinflammatory cytokines and glial markers, indicative of enteric inflammation [36Devos D. et al.Colonic inflammation in Parkinson's disease.Neurobiol. Dis. 2013; 50: 42-48Crossref PubMed Scopus (371) Google Scholar]. Furthermore, patients with inflammatory bowel disease have a higher incidence of PD [37Peter I. et al.Anti–tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease.JAMA Neurol. 2018; 75: 939-946Crossref PubMed Scopus (185) Google Scholar, 38Villumsen M. et al.Inflammatory bowel disease increases the risk of Parkinson's disease: a Danish nationwide cohort study 1977–2014.Gut. 2018; (Published online May 21, 2018)https://doi.org/10.1136/gutjnl-2017-315666Crossref Scopus (163) Google Scholar, 39Lin J.C. et al.Association between Parkinson's disease and inflammatory bowel disease: a nationwide Taiwanese retrospective cohort study.Inflamm. Bowel Dis. 2016; 22: 1049-1055Crossref PubMed Scopus (119) Google Scholar, 40Weimers P. et al.Inflammatory bowel disease and Parkinson's disease: a nationwide Swedish cohort study.Inflamm. Bowel Dis. 2018; (Published online May 16, 2018)https://doi.org/10.1093/ibd/izy190Crossref Scopus (84) Google Scholar], which is substantially reduced by early exposure to anti-inflammatory, antitumor necrosis factor therapy [37Peter I. et al.Anti–tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease.JAMA Neurol. 2018; 75: 939-946Crossref PubMed Scopus (185) Google Scholar]. Systemic inflammation in PD is reflected by elevated serum IL-6, TNF-α, and C-reactive protein, which are associated with severity or faster decline of motor symptoms [41Williams-Gray C.H. et al.Serum immune markers and disease progression in an incident Parkinson's disease cohort (ICICLE-PD).Mov. Disord. 2016; 31: 995-1003Crossref PubMed Scopus (145) Google Scholar]. In addition, there is an increased risk for PD among people who develop type 2 diabetes, especially at younger ages (25–44 years) [42De Pablo-Fernandez E. et al.Association between diabetes and subsequent Parkinson disease: a record-linkage cohort study.Neurology. 2018; (Published online June 13, 2018)https://doi.org/10.1212/WNL.0000000000005771Crossref PubMed Scopus (127) Google Scholar]. Since type 2 diabetes is coupled with systemic inflammation, this might suggest a facilitating role for inflammatory changes in those who happen to be exposed to disease triggers. Furthermore, general immunosuppressive and anti-inflammatory treatments reduce the risk of developing PD [43Racette B.A. et al.Immunosuppressants and risk of Parkinson disease.Ann. Clin. Transl. Neurol. 2018; 5: 870-875Crossref PubMed Scopus (48) Google Scholar]. Taken together, systemic inflammation itself, and several chronic conditions that feature increased inflammation, might be cons