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Heaton et al. investigated the role of LRRK2 mutations in Crohn’s disease (CD) and Parkinson’s disease (PD), focusing on understanding how the N2081D CD-risk variant and G2019S PD-variant lead to different diseases. Using a newly generated knock-in mouse model, they found that the N2081D variant caused more severe inflammation and intestinal damage during induced colitis compared to G2019S and wild-type mice.

The study revealed distinct functional effects of CD- and PD-linked LRRK2 variants. The N2081D mutation specifically enhanced RAB10 phosphorylation, while the G2019S mutation heightened phosphorylation of RAB12 and LRRK2-S1292. Structural analysis suggested that N2081D triggers LRRK2 by disrupting an interdomain interaction between the LRR and kinase regions.

Proteomic analysis revealed increased amounts of proteins linked to immune cell recruitment and activation in N2081D cells following stimulation. The researchers utilised the IonOpticks Aurora Rapid 8×150 XT C18 UHPLC column for LC-MS/MS analysis, enabling high-throughput, high-resolution proteomics.

This study provides an LRRK2-linked CD mouse model and finds the RAB12-LRRK2 pathway to be a potential therapeutic target for CD treatment.

Publication
bioRxiv

Authors

George R. Heaton, Xianting Li, Xiaoting Zhou, Yuanxi Zhang, Duc Tung Vu, Marc Oeller, Ozge Karayel, Quyen Q. Hoang, Meltem Ece Kars, Minghui Wang, Leonid Tarassishin, Matthias Mann, Inga Peter, Zhenyu Yue;

Title

Targeting Specific Kinase Substrates Rescues Increased Colitis Severity Induced by the Crohn’s Disease-Linked LRRK2-N2081D Variant