ArticleThe Biochemical journal2022
Impact of 100 LRRK2 variants linked to Parkinson's disease on kinase activity and microtubule binding.
Article in The Biochemical journal, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers.
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Who cites it
97 citing papers in PubMed, 133 citations in OpenAlex.
- Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson's disease (PD) pathogenesis.Annals of medicine · 2026Review
- Article
- 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
- Addressing the Challenges of Translating LRRK2 Biology into Disease-Modifying Therapies: The LRRK2 Investigative Therapeutics Exchange Initiative.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- LRRK2: Molecular Mechanisms in Parkinson's Disease.International journal of molecular sciences · 2026Review
- Selective loss of primary cilia and neurotrophic signaling in G51D α-synuclein mice highlights a common pathway to Parkinson's disease.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Regulation and roles of mammalian mitophagy.Nature reviews. Molecular cell biology · 2026Review
- Parkinson's disease genetics across diverse ancestries: an observational genetic study of causal and risk variants with translational implications.The Lancet. Neurology · 2026Observational
- Article
- The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair.The EMBO journal · 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
- The structural basis for LRRK2's activation and autoinhibition.bioRxiv : the preprint server for biology · 2026Article
- Proximity proteomics reveals a co-evolved LRRK2-regulatory network linked to centrosomes.EMBO reports · 2026Article
- Lack of Cerebrospinal Fluid α-Synuclein Seeding in VPS35 D620N- and LRRK2 Y1699C-Linked Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Elucidating the molecular interplay between LRRK2 and Rab GTPases.bioRxiv : the preprint server for biology · 2026Article
- Multi-cohort, cross-species urinary proteomics reveals signatures of LRRK2 dysfunction in Parkinson's disease.Molecular systems biology · 2026Article
- Targeting of kinases to treat neurodegenerative diseases.Pharmacological reviews · 2026Review
37 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
Mutations enhancing the kinase activity of leucine-rich repeat kinase-2 (LRRK2) cause Parkinson's disease (PD) and therapies that reduce LRRK2 kinase activity are being tested in clinical trials. Numerous rare variants of unknown clinical significance have been reported, but how the vast majority impact on LRRK2 function is unknown. Here, we investigate 100 LRRK2 variants linked to PD, including previously described pathogenic mutations. We identify 23 LRRK2 variants that robustly stimulate kinase activity, including variants within the N-terminal non-catalytic regions (ARM (E334K, A419V), ANK (R767H), LRR (R1067Q, R1325Q)), as well as variants predicted to destabilize the ROC:CORB interface (ROC (A1442P, V1447M), CORA (R1628P) CORB (S1761R, L1795F)) and COR:COR dimer interface (CORB (R1728H/L)). Most activating variants decrease LRRK2 biomarker site phosphorylation (pSer935/pSer955/pSer973), consistent with the notion that the active kinase conformation blocks their phosphorylation. We conclude that the impact of variants on kinase activity is best evaluated by deploying a cellular assay of LRRK2-dependent Rab10 substrate phosphorylation, compared with a biochemical kinase assay, as only a minority of activating variants (CORB (Y1699C, R1728H/L, S1761R) and kinase (G2019S, I2020T, T2031S)), enhance in vitro kinase activity of immunoprecipitated LRRK2. Twelve variants including several that activate LRRK2 and have been linked to PD, suppress microtubule association in the presence of a Type I kinase inhibitor (ARM (M712V), LRR (R1320S), ROC (A1442P, K1468E, S1508R), CORA (A1589S), CORB (Y1699C, R1728H/L) and WD40 (R2143M, S2350I, G2385R)). Our findings will stimulate work to better understand the mechanisms by which variants impact biology and provide rationale for variant carrier inclusion or exclusion in ongoing and future LRRK2 inhibitor clinical trials.
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