Researchers are finding links between Parkinson’s disease and the gut, and a new genetic study ties the two even closer together. In the January 10 Science Translational Medicine, researchers led by Inga Peter and Judy Cho at Icahn School of Medicine at Mount Sinai, New York, report that several variants in the LRRK2 gene raise or lower risk not only for PD but also for Crohn’s disease, an inflammatory bowel disorder. In particular, the researchers identified a new functional risk variant, N2081D, which boosts LRRK2’s kinase activity, as well as a protective variant that inactivates LRRK2. The findings may provide insight into underlying disease mechanisms and point toward therapeutic approaches, Peter said. For example, LRRK2 inhibitors being developed for PD might help people with Crohn’s disease, while anti-inflammatory approaches could benefit Parkinson’s patients, she suggested.
Other researchers agreed the paper may open up new research avenues. “These data tell us that Parkinson’s is, at least in part, an inflammatory disease,” said Mark Cookson at the National Institutes of Health in Bethesda, Maryland. He added that the findings need to be replicated in large Parkinson’s cohorts.
In 2003, neuroanatomists Heiko Braak and Kelly Del Tredici proposed the controversial idea that an infection in the gut or nose could kick off inflammation and α-synuclein pathology that spreads to the brain (Jul 2011 news series). The idea of a gut-PD link has gained ground, and recently researchers reported changes in intestinal microbiota in early PD, which may accelerate α-synuclein pathology (Dec 2016 news; Bedarf et al., 2017). Crohn’s disease had not been directly linked to PD, although it does associate with variants in the LRRK2 locus (Barrett et al., 2008; Franke et al., 2010; Jostins et al., 2012). These are distinct from the LRRK2 variants, such as G2019S, that predispose people to familial or sporadic PD.
Peter and Cho study Crohn’s disease, and they wanted to find new genetic risk factors that might guide the development of treatments. First author Ken Hui at Yale University School of Medicine, New Haven, Connecticut, combed through exome-sequencing data from 50 people who had Crohn’s disease and were of Ashkenazi Jewish heritage. This population is particularly susceptible to Crohn’s. Hui identified 4,277 new coding variants, which he added to an existing exome chip that queries 230,296 variants in more than 20,000 genes. The authors then used the chip to identify disease associations in 1,477 people with Crohn’s and 2,614 healthy controls, finding three loci with chip-wide significance. Two were known risk factors for Crohn’s, but the third, LRRK2, surprised them. It contained two strong signals: the new variant N2081D, which associated with a nearly twofold higher risk of Crohn’s, and N551K, which correlated with lower risk. N551K and the nearby variants K1423K and R1398H had been reported previously to be inherited together as a protective haplotype for PD (Ross et al., 2011).
The findings suggested to the authors that Crohn’s disease and PD might share some risk factors. To test this idea, they expanded the association study to a total of 6,538 Crohn’s cases and 12,607 healthy controls, and added 5,570 PD cases for comparison. About one-third of this cohort was of Ashkenazi Jewish heritage. As before, N2081D emerged as a strong risk factor for Crohn’s, with an odds ratio of about 1.6. N2081D bumped up PD risk as well, with an odds ratio of 1.3. The protective N551K/R1398H haplotype lowered risk for both diseases, with odds ratios ranging from 0.67 to 0.89. These represent the first coding variants to be linked to both PD and Crohn’s, Cookson noted. The effect of the variants was similar among Jewish and non-Jewish participants, but N2081D was more common in the Ashkenazi Jewish than the general population, with an allele frequency of 8 versus 3 percent.
What does N2081D do? The authors first turned up evidence that this polymorphism accounts for most of the previously reported Crohn’s risk in the LRRK2 locus. When they removed people with N2081D from the genetic analysis, the risk associated with other variants disappeared, suggesting it represented the functional variant. Intriguingly, N2081D resides in the same kinase domain as the major PD risk factor, G2019S. Despite their close spatial occurrence, the two variants exerted independent genetic effects and were not inherited together.
Because G2019S is known to ramp up kinase activity, the authors compared the ability of the two variants to phosphorylate a substrate in cell-free experiments (West et al., 2005). Both N2081D and G2019S bumped up phosphorylation by about 30 percent, indicating similar mechanisms of action. “N2081D is the first functional LRRK2 variant for Crohn’s risk to be identified,” Peter said.
However, the biological effects of N2081D and G2019S are not identical. The former heightens risk for Crohn’s more than PD, while the latter is primarily a PD risk factor with a weak association with Crohn’s as well. Why this difference? Peter believes it may have to do with the substrates LRRK2 interacts with in the cell types most affected in each disease. In the gut, LRRK2 is expressed primarily by macrophages and Paneth cells, specialized epithelial cells of the small intestine that secrete antimicrobial peptides. In this environment, LRRK2 may interact primarily with bacterial peptidoglycans, Peter speculated. In the brain, LRRK2 expression is highest in microglia, and the protein is more likely to phosphorylate brain glycolipids, she added. Thus, the variants may have distinct effects on each substrate.
What about the protective haplotype? Neither the N551K nor R1398H variants affected LRRK2 substrate phosphorylation. However, R1398H occurs in the ROC domain of LRRK2, which helps hydrolyze bound GTP, thereby inactivating the protein. Transfected cells expressing R1398H LRRK2 had more inactive LRRK2 than did those with N551K, N2081D, or G2019S variants. In other words, R1398H switched LRRK2 off. This agrees with a previous report on the variant’s mechanism of action and suggests R1398H represents the functional protective polymorphism (Nixon-Abell et al., 2016). Notably, less-efficient GTP hydrolysis, which keeps LRRK2 on, has been linked to a higher risk of PD (Liao et al., 2014).
The linkage between Parkinson’s and Crohn’s was not limited to N2081D and R1398H. The authors analyzed additional independent variants in the LRRK2 gene that showed up in their large association study. These were weaker signals that did not meet exome chip-wide significance, but associated with both Crohn’s and PD. For 25 out of 29 variants, the risk of Crohn’s and PD moved in the same direction, strengthening the idea that LRRK2 acts similarly in the two disorders.
If Crohn’s and PD share risk factors, the diseases should be more likely to occur together. This is supported by a recent Taiwanese population study of 23 million people that found an increased risk of Parkinson’s in people with Crohn’s disease (Lin et al., 2016). Dana Philpott at the University of Toronto, who studies Crohn’s, told Alzforum that researchers had not previously noticed any increase in Parkinson’s in people with the intestinal disorder. Perhaps because the risk variant is rare, the effect is only visible at the population level, she noted. Peter suggested N2081D could be used to screen people with Crohn’s to find those most at risk of PD.
The finding of shared genetic risk intrigued Michael Schlossmacher at Ottawa Hospital Research Institute, Canada. He noted that LRRK2 variants have been linked not only to PD and Crohn’s, but also to leprosy (Fava et al., 2016). The latter two diseases are both marked by excessive inflammation. In addition, LRRK2 expression in innate immune cells dwarfs that in neurons (Hakimi et al., 2011).
“Maybe LRRK2’s primary role in Parkinson’s is also to regulate inflammation,” Schlossmacher suggested. He recently reported that α-synuclein has antimicrobial effects, while others have found that gut infections stimulate release of α-synuclein (Tomlinson et al., 2017; Stolzenberg et al., 2017). The data support the idea that PD might result from the long-term consequences of a transient infection that touches off chronic inflammation and α-synuclein accumulation in people with certain genetic susceptibilities, Schlossmacher said. He is currently testing the idea in mouse models.
Previous studies have turned up evidence along these lines (Frank-Cannon et al., 2008; Riazi et al., 2008; Jang et al., 2009; Chen et al., 2016). Rudolph Tanzi and Robert Moir at Massachusetts General Hospital, Charlestown, have advanced a similar hypothesis for Alzheimer’s disease (Kumar et al., 2016).
Hui KY, Fernandez-Hernandez H, Hu J, Schaffner A, Pankratz N, Hsu NY, Chuang LS, Carmi S, Villaverde N, Li X, Rivas M, Levine AP, Bao X, Labrias PR, Haritunians T, Ruane D, Gettler K, Chen E, Li D, Schiff ER, Pontikos N, Barzilai N, Brant SR, Bressman S, Cheifetz AS, Clark LN, Daly MJ, Desnick RJ, Duerr RH, Katz S, Lencz T, Myers RH, Ostrer H, Ozelius L, Payami H, Peter Y, Rioux JD, Segal AW, Scott WK, Silverberg MS, Vance JM, Ubarretxena-Belandia I, Foroud T, Atzmon G, Pe’er I, Ioannou Y, McGovern DP, Yue Z, Schadt EE, Cho JH, Peter I. Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci Transl Med. 2018 Jan 10;10(423) PubMed.
Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ, NIDDK IBD Genetics Consortium, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens D, Mni M, Rutgeerts P, Van Gossum A, Zelenika D, Franchimont D, Hugot JP, de Vos M, Vermeire S, Louis E, Belgian-French IBD Consortium, Wellcome Trust Case Control Consortium, Cardon LR, Anderson CA, Drummond H, Nimmo E, Ahmad T, Prescott NJ, Onnie CM, Fisher SA, Marchini J, Ghori J, Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes M, Georges M, Daly MJ. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008 Aug;40(8):955-62. Epub 2008 Jun 29 PubMed.
Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts R, Anderson CA, Bis JC, Bumpstead S, Ellinghaus D, Festen EM, Georges M, Green T, Haritunians T, Jostins L, Latiano A, Mathew CG, Montgomery GW, Prescott NJ, Raychaudhuri S, Rotter JI, Schumm P, Sharma Y, Simms LA, Taylor KD, Whiteman D, Wijmenga C, Baldassano RN, Barclay M, Bayless TM, Brand S, Büning C, Cohen A, Colombel JF, Cottone M, Stronati L, Denson T, De Vos M, D’Inca R, Dubinsky M, Edwards C, Florin T, Franchimont D, Gearry R, Glas J, Van Gossum A, Guthery SL, Halfvarson J, Verspaget HW, Hugot JP, Karban A, Laukens D, Lawrance I, Lemann M, Levine A, Libioulle C, Louis E, Mowat C, Newman W, Panés J, Phillips A, Proctor DD, Regueiro M, Russell R, Rutgeerts P, Sanderson J, Sans M, Seibold F, Steinhart AH, Stokkers PC, Torkvist L, Kullak-Ublick G, Wilson D, Walters T, Targan SR, Brant SR, Rioux JD, D’Amato M, Weersma RK, Kugathasan S, Griffiths AM, Mansfield JC, Vermeire S, Duerr RH, Silverberg MS, Satsangi J, Schreiber S, Cho JH, Annese V, Hakonarson H, Daly MJ, Parkes M. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010 Dec;42(12):1118-25. PubMed.
Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Büning C, Cohain A, Cichon S, D’Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao H, International IBD Genetics Consortium (IIBDGC), Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD, Schadt EE, Daly MJ, Franke A, Parkes M, Vermeire S, Barrett JC, Cho JH. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012 Nov 1;491(7422):119-24. PubMed.
Ross OA, Soto-Ortolaza AI, Heckman MG, Aasly JO, Abahuni N, Annesi G, Bacon JA, Bardien S, Bozi M, Brice A, Brighina L, Van Broeckhoven C, Carr J, Chartier-Harlin MC, Dardiotis E, Dickson DW, Diehl NN, Elbaz A, Ferrarese C, Ferraris A, Fiske B, Gibson JM, Gibson R, Hadjigeorgiou GM, Hattori N, Ioannidis JP, Jasinska-Myga B, Jeon BS, Kim YJ, Klein C, Kruger R, Kyratzi E, Lesage S, Lin CH, Lynch T, Maraganore DM, Mellick GD, Mutez E, Nilsson C, Opala G, Park SS, Puschmann A, Quattrone A, Sharma M, Silburn PA, Sohn YH, Stefanis L, Tadic V, Theuns J, Tomiyama H, Uitti RJ, Valente EM, van de Loo S, Vassilatis DK, Vilariño-Güell C, White LR, Wirdefeldt K, Wszolek ZK, Wu RM, Farrer MJ, Genetic Epidemiology Of Parkinson’s Disease (GEO-PD) Consortium. Association of LRRK2 exonic variants with susceptibility to Parkinson’s disease: a case-control study. Lancet Neurol. 2011 Oct;10(10):898-908. Epub 2011 Aug 30 PubMed.
Nixon-Abell J, Berwick DC, Grannó S, Spain VA, Blackstone C, Harvey K. Protective LRRK2 R1398H Variant Enhances GTPase and Wnt Signaling Activity. Front Mol Neurosci. 2016;9:18. Epub 2016 Mar 8 PubMed.
Liao J, Wu CX, Burlak C, Zhang S, Sahm H, Wang M, Zhang ZY, Vogel KW, Federici M, Riddle SM, Nichols RJ, Liu D, Cookson MR, Stone TA, Hoang QQ. Parkinson disease-associated mutation R1441H in LRRK2 prolongs the “active state” of its GTPase domain. Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):4055-60. Epub 2014 Mar 3 PubMed.
Lin JC, Lin CS, Hsu CW, Lin CL, Kao CH. Association Between Parkinson’s Disease and Inflammatory Bowel Disease: a Nationwide Taiwanese Retrospective Cohort Study. Inflamm Bowel Dis. 2016 May;22(5):1049-55. PubMed.
Hakimi M, Selvanantham T, Swinton E, Padmore RF, Tong Y, Kabbach G, Venderova K, Girardin SE, Bulman DE, Scherzer CR, LaVoie MJ, Gris D, Park DS, Angel JB, Shen J, Philpott DJ, Schlossmacher MG. Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. J Neural Transm. 2011 May;118(5):795-808. PubMed.
To view commentaries, primary articles and linked stories, go to the original posting on Alzforum.org here.
Copyright 1996–2018 Biomedical Research Forum, LLC. All Rights Reserved.