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PubMed:30592011 JSONTXT

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PubMed_ArguminSci

Id Subject Object Predicate Lexical cue
T1 81-238 DRI_Approach denotes Mutations and variations in the leucine-rich repeat kinase 2 (LRRK2) gene are strongly associated with an increased risk to develop Parkinson's disease (PD).
T2 239-360 DRI_Background denotes Most pathogenic LRRK2 mutations display increased kinase activity, which is believed to underlie LRRK2-mediated toxicity.
T3 361-472 DRI_Background denotes Therefore, major efforts have been invested in the development of potent and selective LRRK2 kinase inhibitors.
T4 473-582 DRI_Background denotes Several of these compounds have proven beneficial in cells and in vivo, even in a LRRK2 wild-type background.
T5 583-737 DRI_Background denotes Therefore, LRRK2 kinase inhibition holds great promise as disease-modifying PD therapy, and is currently tested in preclinical and early clinical studies.
T6 738-938 DRI_Background denotes One of the safety concerns is the development of lung pathology in mice and non-human primates, which is most likely related to the strongly reduced LRRK2 protein levels after LRRK2 kinase inhibition.
T7 939-1140 DRI_Challenge denotes In this study, we aimed to better understand the molecular consequences of chronic LRRK2 kinase inhibition, which may be pivotal in the further development of a LRRK2 kinase inhibitor-based PD therapy.
T8 1141-1279 DRI_Outcome denotes We found that LRRK2 protein levels are not restored during long-term LRRK2 kinase inhibition, but are recovered upon inhibitor withdrawal.
T9 1280-1470 DRI_Approach denotes Interestingly, LRRK2 kinase inhibitor-induced destabilization does not occur in all pathogenic LRRK2 variants and the N-terminal part of LRRK2 appears to play a crucial role in this process.
T10 1471-1602 DRI_Approach denotes In addition, we identified CK1, an upstream kinase of LRRK2, as a regulator of LRRK2 protein stability in cell culture and in vivo.
T11 1603-1779 DRI_Outcome denotes We propose that pharmacological LRRK2 kinase inhibition triggers a cascade that results in reduced CK1-mediated phosphorylation of yet unidentified LRRK2 phosphorylation sites.
T12 1780-1876 DRI_Challenge denotes This process involves the N-terminus of LRRK2 and ultimately leads to LRRK2 protein degradation.