MLi-2 / Merck (MSD) - LARVOL DELTA

In-cell cryo-electron tomography reveals differential effects of type I and type II kinase inhibitors on LRRK2 filament formation and microtubule association. (PubMed, Elife) - "In this study, we examine the localization and resulting molecular organization of hyperactive LRRK2-I2020T, a common PD mutant, in HEK 293FT cells treated with type I (MLi-2) or type II (GZD-824) kinase inhibitors. Conversely, treatment with a type II inhibitor resulted in minimal microtubule decoration by LRRK2-I2020T compared to type I inhibitor-treated cells. This study provides a structural framework for understanding how type I and type II kinase inhibitors differentially modulate LRRK2 filament formation, demonstrating that type I inhibitor treatment promotes a distinct filament architecture, whereas such assemblies are not observed with type II inhibitors."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

G2019S LRRK2 Kinase Inhibition in Heterozygous Mice Avoids Lung Phenotype Observed with Inhibition of WT LRRK2. (PubMed, ACS Chem Neurosci) - "This inhibitor did not cause vacuolization in lungs of WT or heterozygous G2019S LRRK2 KI mice but did cause lung toxicity in homozygous G2019S LRRK2 KI mice that was similar to what was observed with the nonselective inhibitor, MLi-2. This study underscores the potential of G2019S LRRK2-selective kinase inhibitors to be safe and effective for heterozygous G2019S LRRK2 PD carriers."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

Inhibition of leucine-rich kinase 2 (LRRK2) promotes peripheral axon regeneration via phosphorylation-network remodelling. (PubMed, Br J Pharmacol) - "These findings identify endogenous, non-pathogenic LRRK2 as a suppressor of axon regeneration. They also support the potential repositioning of small-molecule LRRK2 inhibitors, including clinically advanced compounds and those in preclinical development, as therapeutic strategies to enhance peripheral nerve regeneration."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

A Multistage Virtual Screening Strategy Integrating Molecular Similarity, Deep Learning Scoring, and Molecular Docking toward the Discovery of Novel LRRK2 Inhibitors. (PubMed, J Chem Inf Model) - "The cell viability assay indicated comparable cytotoxicity of compound C-298 to the positive control MLi-2...Molecular dynamics simulations elucidated that hydrogen bond interactions with residues Glu1948 and Ala1950, as well as molecular rigidity, play critical roles in inhibitory activity. Our study demonstrates the utility of AI-assisted virtual screening in accelerating LRRK2 inhibitor discovery and identifies compound C-298 as a promising inhibitor, providing valuable insights for further rational design of LRRK2 inhibitors."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2 • RAB10

Proximity proteomics reveals a co-evolved LRRK2-regulatory network linked to centrosomes. (PubMed, EMBO Rep) - "Furthermore, we identify distinct changes in the LRRK2 proximity proteome that are induced by the type I kinase inhibitor MLi-2 or by co-expression of the LRRK2 upstream effector RAB29. Depending on its activity state and conformation, these protein-protein interactions link LRRK2 to defined cellular sub-compartments, including centriolar satellites and vesicular sub-compartments."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

Preformed fibrils of α-synuclein rapidly activate LRRK2 on early endosomes, driving Rab5 phosphorylation and disrupting endolysosomal and synaptic function. (PubMed, NPJ Parkinsons Dis) - "Pharmacological inhibition of LRRK2 with MLi-2 restores Rab5 activity, lysosomal function, chromatin accessibility, gene expression, and neuronal excitability. Knockdown of Rab5 partially rescues chromatin changes, supporting its role as a downstream effector. These findings identify LRRK2 hyperactivation and the LRRK2-Rab5 axis as key mediators of PFF-induced neuronal dysfunction, highlighting early endosomes as a central platform linking endolysosomal disruption to nuclear responses and offering potential targets for therapeutic intervention in PD."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2 • RAB5A

PHOSPHOPROTEOMIC SCREEN OF ROTENONE TREATED RAT MIDBRAIN AND DSTORM IMAGING REVEALS LRRK2 DEPENDENT PHOSPHORYLATION REGULATION OF ENDOCYTOSIS (ADPD 2026) - "As increased LRRK2 activation is central to both genetic and idiopathic PD pathology, we focused on identifying LRRK2 dependent potential causal mechanisms in PD using neuronal and animal models followed by validation in patient blood samples from the Parkinson's Progression Markers Initiative (PPMI) cohort. We performed Ti-O2-enrichment based phospho-proteomic screens on striatum and substantia nigra collected from rats treated with rotenone as well as on LRRK2-/- or MLi-2-treated midbrain neurons to identify LRRK2 dependent phosphorylation changes contributing to PD pathology... This study revealed LRRK2 dependent AAK1 phosphorylation as a potentially relevant disease mechanism contributing to neurotoxicity by regulating CME."

Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • AP2M1 • LRRK2

MULTI-COHORT, CROSS-SPECIES URINARY PROTEOMICS REVEALS SIGNATURES OF LRRK2 DYSFUNCTION IN PARKINSON'S DISEASE (ADPD 2026) - "Together, our study establishes urine as a non-invasive matrix capturing PD-linked signatures of LRRK2 dysfunction and provides candidate pharmacodynamic LRRK2 markers."

CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

Climbing fibres recruit disinhibition to enhance Purkinje cell calcium signals. (PubMed, Nature) - "Serial electron microscopy reconstructions indicate that CFs contact both MLI subtypes without making conventional synapses, but more CFs contact each MLI2 through more sites with larger contact areas...This balance was robustly shifted towards MLI1 suppression when CFs were synchronously active, in turn elevating the PC dendritic calcium signals necessary for long-term depression. These data provide mechanistic insight into why CF synchrony can be highly effective at inducing cerebellar learning2,3 by revealing a critical disinhibitory circuit that allows CFs to act through MLIs to enhance PC dendritic calcium signals necessary for plasticity."

Journal • CNS Disorders • Depression • Psychiatry

Membrane Dysfunction as a Central Mechanism in LRRK2-Associated Parkinson's Disease: Comparative Analysis of G2019S and I1371V Variants. (PubMed, Cells) - "Pharmacological intervention revealed mutation-specific responses, with the non-selective LRRK2 modulator GW5074 outperforming the kinase-selective inhibitor MLi-2 in restoring Rab8A phosphorylation, membrane integrity, and dopaminergic function. Collectively, these findings identify membrane lipid dysregulation as a central cell biological mechanism in LRRK2-associated PD and underscore the importance of variant-specific therapeutic strategies."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • CAV1 • LRRK2 • RAB10

Multi-cohort, cross-species urinary proteomics reveals signatures of LRRK2 dysfunction in Parkinson's disease. (PubMed, Mol Syst Biol) - "To evaluate translation, we performed multi-organ and urinary proteomics in rat gain- and loss-of-function models (BAC-LRRK2G2019S and Lrrk2KO) and after Lrrk2 inhibition (MLi-2 and PF-475), revealing tissue-specific responses-strongest in kidney-and cross-species overlap, including 24 brain proteins detectable in human urine. Rat-derived perturbations predicted LRRK2 mutation status in patients (AUC 0.75) and reversed with Lrrk2 inhibition, supporting their pharmacodynamic utility. Together, our findings establish urine as a scalable, non-invasive matrix that captures systemic and brain-relevant consequences of LRRK2 dysfunction and nominate candidate pharmacodynamic markers set to support LRRK2-directed trials."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

Purkinje cell collaterals preferentially target a subtype of molecular layer interneuron. (PubMed, J Neurosci) - "We also found that candelabrum cells (a type of PLI) preferentially inhibit MLI1s. These findings suggest that PC-PC synapses, the PC-MLI2-MLI1-PC pathway and the PC-candelabrum cell-MLI1-PC pathway act together to allow alterations in PC firing to provide negative feedback to other PCs."

Journal

Interferon gamma stimulates coordinated changes in LRRK2, GCase, and cathepsin activities in idiopathic and genetic Parkinson's disease monocytes. (PubMed, NPJ Parkinsons Dis) - "Cells were stimulated with interferon gamma, which strongly induces expression of the LRRK2 protein, and treated with and without the LRRK2 kinase inhibitor MLi-2...Interferon gamma stimulation had marked effects on LRRK2 levels and phosphorylation of the LRRK2 substrate Rab10, as well as effects on the expression of HLA-DR and cathepsin activity, with some mutation-specific and monocyte-type-specific outcomes. These results help to advance understanding of how risk genes may interact with immune stimuli in the context of PD."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • IFNG • LRRK2 • RAB10

Parkinson's-Linked LRRK2 and GBA1 Mutations Modulate the Peripheral Immune Response to Pseudomonas aeruginosa. (PubMed, Mov Disord) - "This work demonstrates that PD-linked mutations in LRRK2 and GBA1 converge on peripheral blood immune cell dysregulation, as evinced by the ability of LRRK2 inhibitors and GCase activators to modulate the ex vivo immune response to bacterial exposure."

Journal • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • GBA • GBA1 • IL1B • LRRK2

Climbing fibers selectively recruit disinhibitory interneurons to enhance dendritic calcium signaling in cerebellar Purkinje cells. (Neuroscience 2025) - "Serial EM reconstructions indicate that CFs contact both MLI subtypes without making conventional synapses, but more CFs contact each MLI2 via more sites with larger contact areas...This balance was robustly shifted toward MLI1 suppression when CFs were synchronously active, in turn elevating the PC dendritic calcium signals necessary for LTD. These data provide mechanistic insight into why CF synchrony can be highly effective at inducing cerebellar learning2,3 by revealing a critical disinhibitory circuit that allows CFs to act through MLIs to enhance PC dendritic calcium signals necessary for plasticity."

CNS Disorders

Early and persistent rescue of corticostriatal LTP by in vivo MLi-2 administration in mice carrying a Parkinson's linked LRRK2G2019S mutation (Neuroscience 2025) - "Ongoing experiments are assessing if inhibitor-based rescue of LTP is associated with normalized surface GluA1 levels and activity-dependent trafficking, and if the timing of in vivo-based inhibitor exposure that rescues LTP conforms to a critical period (versus multiple sensitive periods) of intervention. Together, these experiments suggest that mutation-driven alterations in molecular trafficking necessary for dynamic synaptic signaling are the culmination of durable changes that take weeks of inhibitor exposure to normalize."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Movement Disorders • Parkinson's Disease • CDKN1A • LRRK2

Association between lysosomal hydrolase activity and LRRK2 kinase activity in induced pluripotent stem cell-derived dopaminergic neurons of patients with GBA-associated Parkinson’s disease (SSIEM 2023) - "The prospect of using LRRK2 inhibitors for the treatment of Parkinson`s disease associated with mutations in the GBA gene (GBA-PD) now is discussed due to the fact that inhibition of LRRK2 activity by selective inhibitor MLi-2 has previously been shown to increase the activity of the glucocerebrosidase (GCase) enzyme...Our results suggest a role for LRRK2 in the regulation of not only the activity of GCase, but also of other lysosomal enzymes. Our results open up new horizons for therapy GBA-PD and it also is interesting to explore the possibility of using this inhibitor for LSDs as well."

Clinical • CNS Disorders • Gaucher Disease • Lysosomal Storage Diseases • Metabolic Disorders • Movement Disorders • Parkinson's Disease • Pompe Disease • Rare Diseases • GBA • IDUA • LRRK2 • RAB10

ENDOLUMINAL FUNCTIONAL LUMEN IMAGING PROBE IN THE FUNCTIONAL ASSESSMENT OF PYLORIC SPHINCTER IN GASTROPARESIS: A SYSTEMATIC REVIEW WITH META-ANALYSIS OF NORMATIVE VALUES (UEGW 2025) - "FLIP metrics pooled mean values at different fill volumes at baseline in gastroparesis patientsPooled mean values#30 mLI2(%)40 mLI2(%)50 mLI2(%)DI (mm2/mmHg)7.5 (6.1-8.9)388.9 (7.5-10.4)83.47.1 (6.1-8.1)88.1CSA (mm2)85.5 (75.4-95.6)0125.3 (108.3-142.3)78195.7 (175.5-215.9)70Dmin (mm)10.7 (9.1-12.3)8513.4 (12.1-14.7)9216.5 (15.7-17.3)80P (mmHg)15.0 (11.3-18.7)7718.8 (16.5-21.1)7434.0 (29.2-38.8)91#Values are expressed as pooled means and 95% CIsCIs Confidence Intervals CSA Cross-Sectional Area DI Distensibility Index Dmin Minimum Diameter FLIP Functional Lumen Imaging Probe P Pressure This is the first systematic effort in gathering evidence on FLIP in gastroparesis... This is the first systematic effort in gathering evidence on FLIP in gastroparesis. CSA and DI significantly changed after pylorus-targeted treatments. Normative values displayed substantial heterogeneity and wide CIs."

Retrospective data • Review • Dyspepsia • Gastrointestinal Disorder

EXACERBATED CELLULAR SENESCENCE IN HUMAN DOPAMINERGIC NEURONS ALONG WITH AN INCREASE IN LRRK2 KINASE ACTIVITY. (WCN 2025) - "Overall, inhibiting LRRK2 may provide a beneficial strategy for managing PD."

CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2 • RAB10

Selective Stabilization of LRRK2 Kinase Conformations Reveals Distinct Modes of Action for Type I and II Inhibitors. (PubMed, Cell Biochem Biophys) - No abstract available

Journal • LRRK2

Restoration of Lysosomal Hydrolase Activities by LRRK2 Inhibition in GBA1- and LRRK2-Associated Parkinson's Disease Patient-Derived Cells. (PubMed, J Neurochem) - "Moreover, LRRK2 inhibition also enhances the activity of other lysosomal hydrolases. Our findings expand the understanding of the molecular mechanism of LRRK2 inhibitors, offering valuable insights for further development of PD treatments."

Journal • CNS Disorders • Movement Disorders • Neuroblastoma • Oncology • Parkinson's Disease • Solid Tumor • CTSD • GBA1 • LAMP2 • LRRK2

Purkinje cell collaterals preferentially target a subtype of molecular layer interneuron. (PubMed, bioRxiv) - "We also found that candelabrum cells (a type of PLI) preferentially inhibit MLI1s. These findings establish that PC-PC synapses, the PC-MLI2-MLI1-PC pathway and the PC-candelabrum cell-MLI1-PC pathway act together to allow alterations in PC firing to provide negative feedback to other PCs."

Journal

Climbing fibers selectively recruit disinhibitory interneurons to enhance dendritic calcium signaling in cerebellar Purkinje cells. (PubMed, bioRxiv) - "Serial EM reconstructions indicate that CFs contact both MLI subtypes without making conventional synapses, but more CFs contact each MLI2 via more sites with larger contact areas...This balance was robustly shifted toward MLI1 suppression when CFs were synchronously active, in turn elevating the PC dendritic calcium signals necessary for LTD. These data provide mechanistic insight into why CF synchrony can be highly effective at inducing cerebellar learning 2,3 by revealing a critical disinhibitory circuit that allows CFs to act through MLIs to enhance PC dendritic calcium signals necessary for plasticity."

Journal

Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinson's disease-linked LRRK2-mutant mice. (PubMed, Sci Signal) - "Furthermore, MLi-2 increased the density of fine striatal dopaminergic processes and decreased the amount of stress-associated Sonic Hedgehog RNA expression in nigral dopaminergic neurons. Thus, pathogenic LRRK2-driven cilia loss is reversible in postmitotic neurons and astrocytes, which suggests that early administration of specific LRRK2 inhibitors may therapeutically benefit patients."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2 • SHH

Striatal cell-type-specific molecular signatures reveal potential therapeutic targets in a model of dystonia. (PubMed, Neurobiol Dis) - "The pattern of mRNA dysregulation was distinct from parkinsonism where the dopamine deficit occurs in adults, suggesting that the phenotypic outcome is dependent on both the timing of the dopaminergic deficit and the SPN-specific adaptions. By leveraging these disease-specific molecular signatures, we identified LRRK2 inhibition, among other mechanisms, as a novel therapeutic target for dystonia."

Journal • CNS Disorders • Dystonia • Movement Disorders • Parkinson's Disease • LRRK2