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.

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  1. Regarding the paper by Hui et al., LRRK2 was implicated in inflammation and specifically Crohn's disease about half a decade ago. It is interesting and novel that they have identified N2081D as a risk factor for Crohn's disease and R1398H as a protective mutant. 

    On the potential connection between Parkinson’s disease etiology and that of the gut, the authors reasoned that since N2081 resides within the kinase domain of LRRK2, as does the Parkinson's disease-associated mutation G2019S, it might also affect the kinase activity of LRRK2 in similar ways. This is a reasonable initial hypothesis, however, residue G2019 resides precisely in the active site of LRRK2 (based on a homology model) and residue N2081 resides in the distal side of the C-lobe, which is far away from the active site and pointing into the solvent, rendering it unlikely to have any direct effects on the active site or substrate-binding site of LRRK2. However, in the western blot assay showing that N2018D increased phosphorylation of Rab10 (figure 4B), the difference in activity between N2018D LRRK2 and that of WT is small (less than 0.5), and western blots are prone to sample-to-sample variability in that range.

    Likewise, in the GTPase activity assay (figure 4C) R1398H LRRK2 activity is only slightly higher than that of WT (less than 0.5) and the TLC assay, due to smearing effects and high background, is prone to high background errors.

    Overall, the paper raises an interesting possibility that Crohn's disease and Parkinson's disease might potentially share the same pathogenic mechanism; however, this would need to be confirmed with additional evidence.

    View all comments by Quyen Hoang

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  1. Genetic Findings Link Parkinson’s to Crohn’s Disease, Inflammation