Functional properties of LRRK2 mutations in Taiwanese Parkinson disease Kuo-Hsuan Chang, Chiung-Mei Chen, Chih-Hsin Lin, Wen-Teng Chang, Pei-Ru Jiang,

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Functional properties of LRRK2 mutations in Taiwanese Parkinson disease Kuo-Hsuan Chang, Chiung-Mei Chen, Chih-Hsin Lin, Wen-Teng Chang, Pei-Ru Jiang, Ya-Chin Hsiao, Yih-Ru Wu, Guey-Jen Lee-Chen Journal of the Formosan Medical Association Volume 116, Issue 3, Pages 197-204 (March 2017) DOI: 10.1016/j.jfma.2016.04.009 Copyright © 2016 Terms and Conditions

Figure 1 LRRK2 domain structure and GTP-binding activities of wild-type and mutated LRRK2. (A) Schematic diagram of LRRK2 multidomains structure. ANK = ankyrin repeat region; COR=C terminal of Ras; LRR = leucine-rich repeat domain; LRRK2 = leucine-rich repeat kinase 2; MAPKKK = mitogen-activated protein kinase kinase kinase; ROC = Ras of complex protein (GTPase); WD40 = WD40 repeats. The locations of the studied mutations are shown above. The estimated domain boundaries are indicated by the residue numbers beneath. (B) Myc-tagged wild-type (WT), p.R767H (767), p.S885N (885), p.R1441H (1441), and p.G2019S (2019) LRRK2 were transfected into 293 cells and GTP-bound LRRK2 level was assessed with anti-Myc antibody. Binding ratio of LRRK2 variants was compared to the wild-type LRRK2. Mock transfection was used as a negative control. Blots are representative of three independent experiments. Data were normalized to WT. *p < 0.05 in comparison with wild-type LRRK2. Journal of the Formosan Medical Association 2017 116, 197-204DOI: (10.1016/j.jfma.2016.04.009) Copyright © 2016 Terms and Conditions

Figure 2 Expression of EGFP-tagged LRRK2 proteins in 293 cells. (A) Western blot analysis of 293 cells transiently expressing wild-type (WT), p.R767H (767), p.S885N (885), p.R1441H (1441), and p.G2019S (2019) LRRK2 using LRRK2 and β-actin antibodies. (B) Representative fluorescence microscopy images of LRRK2-EGFP expression after 2 days transfection. (C) Inclusion analysis of LRRK2-EGFP cells. *p < 0.05 and **p < 0.01, comparison between wild-type and mutated LRRK2. Journal of the Formosan Medical Association 2017 116, 197-204DOI: (10.1016/j.jfma.2016.04.009) Copyright © 2016 Terms and Conditions

Figure 3 Confocal microscopy examination of α-synuclein protein in SK-N-SH cells coexpressing wild-type (WT) and p.R767H, p.S885N, p.R1441H, and p.G2019S mutant LRRK2. Journal of the Formosan Medical Association 2017 116, 197-204DOI: (10.1016/j.jfma.2016.04.009) Copyright © 2016 Terms and Conditions

Figure 4 ARHGEF7 interaction between wild-type and mutated LRRK2. Myc-His-tagged wild-type (WT), p.R767H (767), p.S885N (885), p.R1441H (1441), and p.G2019S (2019) LRRK2 were cotransfected with V5-His-tagged ARHGEF7 in 293 cells and subjected to V5 coimmunoprecipitation (IP). Transfection with empty V5 vector was used as a negative control (−). Immunoblotting was performed using antibodies against V5 and Myc, respectively. The interaction strength of ARHGEF7 was compared between wild-type and mutants LRRK2. Blots are representative of three independent experiments. Data were normalized to WT. *p <0.05 in comparison with wild-type LRRK2. Journal of the Formosan Medical Association 2017 116, 197-204DOI: (10.1016/j.jfma.2016.04.009) Copyright © 2016 Terms and Conditions