ArticleThe Biochemical journal2021
Impact of Type II LRRK2 inhibitors on signaling and mitophagy.
Article in The Biochemical journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 67 citations in OpenAlex.
- Parkinson's disease-associated LRRK2 risk variant, G2385R, enhances Rab substrate phosphorylation and impairs neuronal integrity.Human molecular genetics · 2026Article
- Chemical Genetic Targeting of the LRRK2 GTPase Domain.bioRxiv : the preprint server for biology · 2026Article
- Constrained peptide mimics of the LRRK2 C-terminal Helix inhibits its kinase activity.Bioorganic chemistry · 2026Article
- LRRK2: Molecular Mechanisms in Parkinson's Disease.International journal of molecular sciences · 2026Review
- Article
- An LRRK2 variant blocks NCOA4 trafficking upon iron overload, leading to ferroptotic death.Journal of cell science · 2026Article
- VPS35 mutation inhibits PINK1/parkin-mediated mitophagy via increased LRRK2 kinase activity.Brain : a journal of neurology · 2026Article
- Ex Vivo LRRK2 Activation in Asian G2385R and R1628P Variant Carriers and Idiopathic Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Large-scale functional annotation establishes a reference framework for humanmedRxiv : the preprint server for health sciences · 2026Article
- Proximity proteomics reveals a co-evolved LRRK2-regulatory network linked to centrosomes.EMBO reports · 2026Article
- Pathological Protein Targets in Parkinson's Disease: Progress Towards the Development of Disease-Modifying Therapies.CNS drugs · 2026Review
- Role of LRRK2 in physiological activities, diseases, and therapy.Chinese medical journal · 2026Review
- Selective Stabilization of LRRK2 Kinase Conformations Reveals Distinct Modes of Action for Type I and II Inhibitors.Cell biochemistry and biophysics · 2026Article
- Regulation of LRRK2 activity by metabolic stress and heavy metal exposure.Brain research · 2025Article
- Tau uptake by human neurons depends on receptor LRP1 and kinase LRRK2.The EMBO journal · 2025Article
- Type II kinase inhibitors that target Parkinson's disease-associated LRRK2.Science advances · 2025Article
- Leucine-rich repeat kinase 2 biomarkers for Parkinson's disease.The Biochemical journal · 2025Review
- LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.The Biochemical journal · 2025Review
- Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Editorial: The contribution of autophagy to neuronal metabolism.Frontiers in cell and developmental biology · 2025Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Much effort has been devoted to the development of selective inhibitors of the LRRK2 as a potential treatment for LRRK2 driven Parkinson's disease. In this study, we first compare the properties of Type I (GSK3357679A and MLi-2) and Type II (GZD-824, Rebastinib and Ponatinib) kinase inhibitors that bind to the closed or open conformations of the LRRK2 kinase domain, respectively. We show that Type I and Type II inhibitors suppress phosphorylation of Rab10 and Rab12, key physiological substrates of LRRK2 and also promote mitophagy, a process suppressed by LRRK2. Type II inhibitors also display higher potency towards wild-type LRRK2 compared with pathogenic mutants. Unexpectedly, we find that Type II inhibitors, in contrast with Type I compounds, fail to induce dephosphorylation of a set of well-studied LRRK2 biomarker phosphorylation sites at the N-terminal region of LRRK2, including Ser935. These findings emphasize that the biomarker phosphorylation sites on LRRK2 are likely reporting on the open vs closed conformation of LRRK2 kinase and that only inhibitors which stabilize the closed conformation induce dephosphorylation of these biomarker sites. Finally, we demonstrate that the LRRK2[A2016T] mutant which is resistant to MLi-2 Type 1 inhibitor, also induces resistance to GZD-824 and Rebastinib suggesting this mutation could be exploited to distinguish off target effects of Type II inhibitors. Our observations provide a framework of knowledge to aid with the development of more selective Type II LRRK2 inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.