MLi-2 / Merck (MSD) - LARVOL DELTA

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

PHOSPHOPROTEOMIC SCREEN OF ROTENONE TREATED RAT MIDBRAIN AND DSTORM IMAGING REVEALS LRRK2 DEPENDENT PHOSPHORYLATION REGULATION OF ENDOCYTOSIS (ADPD 2026) - " 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

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

MILD HYPEREMIA IN THE ABSENCE OF BOWEL WALL THICKENING ON INTESTINAL ULTRASOUND IS ASSOCIATED WITH BIOCHEMICAL DISEASE ACTIVITY AND WORSE DISEASE OUTCOMES IN PATIENTS WITH CROHN'S DISEASE AND ULCERATIVE COLITIS (DDW 2025) - "We excluded pts with mLim2 or 3, BWT >3mm anywhere on index IUS, or mLim1 at surgical anastomoses only...Although PDO in UC was numerically higher in mLim1, this was not statistically significant likely due to small cohort size. These findings support the consideration of treatment adjustments when this isolated parameter is identified and inform future IUS treat-to-target strategies."

Clinical • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • CRP

Expanding Therapeutic Horizons with Indazole-Based Compounds: A Review of Anticancer, Antimicrobial, and Neuroprotective Applications. (PubMed, Med Chem) - "Additionally, the LRRK2 antagonist MLi-2 demonstrated remarkable efficacy in treating neurodegenerative diseases, while indazole-5-carboxamides exhibited a strong affinity for monoamine oxidases, potentially offering new therapeutic options for Parkinson's disease. Inhibition of COX-2 and FGFR resulted in anti-inflammatory effects, with minimal off-target damage observed in vivo. Collectively, our findings underscore the therapeutic versatility of indazole frameworks across various disease pathways, suggesting their potential for developing innovative treatments for cancer, infections, metabolic disorders, and neurological conditions."

Journal • Breast Cancer • CNS Disorders • Genetic Disorders • Hepatocellular Cancer • Hepatology • HER2 Breast Cancer • HER2 Positive Breast Cancer • Infectious Disease • Metabolic Disorders • Movement Disorders • Obesity • Oncology • Parkinson's Disease • Solid Tumor • CDC37 • CDK2 • EGFR • HER-2 • HSP90AA1 • KDR • LRRK2 • MET

ACUTE KNOCKDOWN OF LRRK2 INCREASES SYNAPTIC-VESICLE SIZE AND AUGMENTS EXOCYTOSIS. ** WITHDRAWN BY AUTHOR** (ADPD 2025) - "These effects are unlikely to be due to inhibition of Lrrk2 kinase activity, because treating neurons with a highly selective kinase inhibitor (MLi-2) did not result in similar phenotypes... Our data advocate a structural, non-enzymatic role of Lrrk2 in modulating membranes at synapses and provide new insights into its physiologic role. Specific domaisn leading to these phenotypes are currently being investigated."

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

Effect of LRRK2 Inhibition on the Activity of Glucocerebrosidase in Patient-Specific Cells from Patients with Gaucher Disease. (PubMed, Biochemistry (Mosc)) - "The activity of GCase and the levels of its substrate in cells cultured with and without MLi-2 was assayed by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). No effect of LRRK2 inhibition on the activity GCase in a group of patients with GD was found."

Journal • CNS Disorders • Gaucher Disease • Genetic Disorders • Metabolic Disorders • Movement Disorders • Parkinson's Disease • GBA1 • LRRK2

In-depth mass-spectrometry reveals phospho-RAB12 as a blood biomarker of G2019S LRRK2-driven Parkinson's disease. (PubMed, Brain) - "Freshly collected PBMCs from 3 G2019S L2PD, 1 R1441G L2PD, 1 iPD, and 5 controls (n=10) showed strong diminishment of pSer106 RAB12 phosphorylation levels after in-vitro administration of the MLi-2 LRRK2 inhibitor...Our data suggest that monitoring pSer106 RAB12 phosphorylation could be a relevant biomarker for tracking LRRK2 activation, particularly in G2019S carriers. Future work may determine whether pSer106 RAB12 could help with patient enrichment and monitoring drug efficacy in LRRK2 clinical trials."

Biomarker • Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • LAMP1 • LRRK2

The kinase LRRK2 is required for the physiological function and expression of the glial glutamate transporter EAAT2 (SLC1A2). (PubMed, J Neurochem) - "The results show that EAAT2 expression and function are impaired in the absence of the kinase and also under its pharmacological inhibition via MLi-2 treatment...This study, for the first time, demonstrates the physiological importance of LRRK2 in EAAT2 function, highlighting the specificity of LRRK2-mediated modulation of EAAT2 and suggesting a potential role for the kinase as a checkpoint for preserving neurons from excitotoxicity. In brain conditions associated with impaired glutamate clearance, targeting LRRK2 for EAAT2 regulation may offer novel therapeutic opportunities."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease • LRRK2 • SLC1A2

LRRK2 and RAB8A regulate cell death after lysosomal damage in macrophages through cholesterol-related pathways. (PubMed, Neurobiol Dis) - "U18666A-treated cells were less sensitive to LLOMe-induced cell death, but the attenuation of cell death by LRRK2 inhibition was strongly reduced suggesting that LRRK2 inhibition and lysosomal cholesterol reduces cell death by overlapping mechanisms. Thus, our data demonstrates a LRRK2- and RAB8A-mediated attenuation of RAW 264.7 cell death induced by lysosomal damage that is modulated by lysosomal cholesterol."

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

Metagenomic Insights into Coal Slag Remediation Effects on Soil and Microbial Health in Qinghai's Muli Coal Mine. (PubMed, Microorganisms) - "From the perspective of overall ecological restoration, this study concluded that the MLII2 treatment group exhibited the most favorable ecological restoration outcomes. This finding emphasizes the importance of not only enhancing microbial diversity but also prioritizing the restoration of community functions, especially for the recovery of fragile high-altitude ecosystems."

Journal