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LRRK2
LRRK2
LRRK2
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LRRK2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesLRRK2, AURA17, DARDARIN, PARK8, RIPK7, ROCO2, leucine-rich repeat kinase 2, leucine rich repeat kinase 2
External IDsOMIM: 609007; MGI: 1913975; HomoloGene: 18982; GeneCards: LRRK2; OMA:LRRK2 - orthologs
EC number2.7.11.1
Orthologs
SpeciesHumanMouse
Entrez

120892

66725

Ensembl

ENSG00000188906

ENSMUSG00000036273

UniProt

Q5S007

Q5S006

RefSeq (mRNA)

NM_198578

NM_025730

RefSeq (protein)

NP_940980

NP_080006

Location (UCSC)Chr 12: 40.2 – 40.37 MbChr 15: 91.56 – 91.7 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Leucine-rich repeat kinase 2 (LRRK2), also known as dardarin (from the Basque word "dardara" which means trembling) and PARK8 (from early identified association with Parkinson's disease), is a large, multifunctional kinase enzyme that in humans is encoded by the LRRK2 gene.[5][6] LRRK2 is a member of the leucine-rich repeat kinase family. Variants of this gene are associated with an increased risk of Parkinson's disease and Crohn's disease.[5][6]

Function

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The LRRK2 gene encodes a protein with an armadillo repeats (ARM) region, an ankyrin repeat (ANK) region, a leucine-rich repeat (LRR) domain, a kinase domain, a RAS domain, a GTPase domain, and a WD40 domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane.

LRRK2 interacts with the C-terminal R2 RING finger domain of parkin, and parkin interacted with the COR domain of LRRK2. Expression of mutant LRRK2 induced apoptotic cell death in neuroblastoma cells and in mouse cortical neurons.[7]

Expression of LRRK2 mutants implicated in autosomal dominant Parkinson's disease causes shortening and simplification of the dendritic tree in vivo and in cultured neurons.[8] This is mediated in part by alterations in macroautophagy,[9][10][11][12][13] and can be prevented by protein kinase A regulation of the autophagy protein LC3.[14] The G2019S and R1441C mutations elicit post-synaptic calcium imbalance, leading to excess mitochondrial clearance from dendrites by mitophagy.[15] LRRK2 is also a substrate for chaperone-mediated autophagy.[16]

Disease-associated mutant alleles of LRRK2 (R1441C, G2019S, I2020T) generally show elevated kinase activity.[17][18]

LRRK2 activity has been tied to generation of reactive-oxygen species (ROS) which are associated with Parkinson's disease pathogenesis. This activity is dependent on LRRK2-mediated phosphorylation of NADPH oxidase 2 (NOX2). Specifically, LRRK2 activity promotes activatory phosphorylation of the p47phox subunit of NOX2 at S345.[19]

Clinical significance

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Mutations in this gene have been associated with Parkinson's disease type 8.[20][21]

The G2019S mutation results in enhanced kinase activity, and is a relatively common cause of familial Parkinson's disease in Caucasians.[22] It may also cause sporadic Parkinson's disease. The mutated Gly amino acid is conserved in all kinase domains of all species.

The G2019S mutation is one of a small number of LRRK2 mutations proven to cause Parkinson's disease. Of these, G2019S is the most common in the Western World, accounting for ~2% of all Parkinson's disease cases in North American Caucasians. This mutation is enriched in certain populations, being found in approximately 20% of all Ashkenazi Jewish Parkinson's disease patients and in approximately 40% of all Parkinson's disease patients of North African Berber Arab ancestry.[23][24]

Unexpectedly, genome-wide association studies have found an association between LRRK2 and Crohn's disease as well as with Parkinson's disease, suggesting that the two diseases share common pathways.[25][26]

Attempts have been made to grow crystals of the LRRK2 aboard the International Space Station, as the low-gravity environment renders the protein less susceptible to sedimentation and convection, and thus more crystallizable.[27]

Mutations in the LRRK2 gene is the main factor in contributing to the genetic development of Parkinson's disease, and over 100 mutations in this gene have been shown to increase the chance of PD development. These mutations are most commonly seen in North African Arab Berber, Chinese, and Japanese populations.[28]

Therapeutics development

[edit]

Multiple preclinical studies have found that inhibition or silencing of LRRK2 may be therapeutically beneficial for treatment of Parkinson's disease.[29][30] There have been efforts to develop therapeutics for Parkinson's disease targeting LRRK2, including LRRK2 inhibitors[31][32] and antisense oligonucleotides (ASOs) targeting LRRK2.[33]

References

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Further reading

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

LRRK2

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from Grokipedia
LRRK2, or leucine-rich repeat kinase 2, is a large multidomain protein encoded by the PARK8 gene on human chromosome 12, comprising 2527 amino acids and belonging to the ROCO family of proteins characterized by their Ras-like GTPase (ROC) and C-terminal of ROC (COR) domains. This protein features several key structural elements, including N-terminal armadillo (ARM) and ankyrin (ANK) repeats for protein interactions, central leucine-rich repeats (LRR) for substrate binding, the ROC-COR tandem for GTPase activity, a serine/threonine kinase domain responsible for phosphorylation, and C-terminal WD40 repeats that mediate complex assembly. LRRK2 exhibits dual enzymatic functions as both a GTPase, hydrolyzing GTP to regulate its activation state, and a kinase, phosphorylating substrates such as Rab GTPases (e.g., Rab8A, Rab10, and Rab12) to influence cellular processes. Physiologically, LRRK2 is widely expressed in the brain, kidneys, lungs, and immune cells, where it plays critical roles in membrane trafficking, lysosomal homeostasis, autophagy-lysosomal pathway regulation, synaptic vesicle endocytosis, and cytoskeletal dynamics, often localizing to organelles like the trans-Golgi network and endosomes. Pathologically, mutations in LRRK2 represent the single most common genetic cause of late-onset familial (PD), accounting for up to 5-13% of autosomal dominant cases in certain populations, and are also associated with increased risk in sporadic PD. Several LRRK2 variants (approximately seven to eight) have been identified as pathogenic, with the G2019S mutation in the domain being the most prevalent globally, enhancing activity and leading to hyperphosphorylation of substrates that disrupt neuronal integrity. Other notable mutations, such as R1441C/G/H in the ROC domain and I2020T in the domain, similarly elevate function or impair activity, resulting in neurodegeneration through mechanisms including α-synuclein aggregation, hyperphosphorylation, lysosomal dysfunction, mitochondrial impairment, and neuroinflammatory responses via microglial activation. These alterations affect pathways intersecting with other PD-related proteins, underscoring LRRK2's central role in both genetic and idiopathic forms of the disease. As a promising therapeutic target, LRRK2 inhibition has shown potential in preclinical models to mitigate PD pathology by restoring lysosomal function and reducing toxic protein accumulation, with ongoing clinical trials, such as phase 2 studies evaluating BIIB122 as of 2025, assessing inhibitors for disease modification. Recent research highlights LRRK2's involvement in immune regulation and ciliogenesis, expanding its relevance beyond neurodegeneration to broader cellular .

Gene and Structure

Gene Location and Expression

The LRRK2 gene is located on the long arm of human chromosome 12 at the q12 cytogenetic band (12q12). It spans approximately 144 kilobases (kb) of genomic DNA and consists of 51 exons. The gene encodes the protein dardarin, a large multidomain kinase. The LRRK2 gene undergoes alternative splicing, producing multiple transcript variants, with at least 22 distinct isoforms identified in humans. The canonical transcript, ENST00000298910, includes all 51 exons and encodes the full-length 2,527-amino-acid protein. LRRK2 is ubiquitously expressed across tissues, with the highest levels observed in the —particularly in the and —, and immune cells such as B-lymphocytes and neutrophils. Its tissue-specific expression is regulated by promoter elements, including a core promoter responsive to the , as well as distal enhancers that modulate activity in neural and immune contexts. The LRRK2 gene exhibits strong evolutionary conservation among mammals, with functional orthologs present in such as mice (Lrrk2) and rats, sharing high similarity in key domains. More distantly, it belongs to the Roco protein family, with homologs like GbpC in the amoebozoan Dictyostelium discoideum, highlighting ancient origins of the ROCO kinase-GTPase architecture.

Protein Domains and Architecture

LRRK2 is a large multidomain protein consisting of 2,527 with a molecular weight of approximately 286 kDa. It functions as a homodimer in solution, with a experimentally determined of around 581 kDa, as confirmed by analysis. This dimeric assembly is primarily mediated by interfaces in the C-terminal of ROC (COR) domain, contributing to its overall stability and regulatory interactions. The domain architecture of LRRK2 is organized from the N-terminus to the C-terminus as follows: armadillo (ARM) repeats, which facilitate protein-protein interactions; ankyrin (ANK) repeats; leucine-rich repeats (LRR), involved in ligand binding; the Ras of complex proteins (ROC) GTPase domain; the COR linker domain; a kinase domain; and a C-terminal propeller domain that serves as a scaffolding module. This linear arrangement forms a complex, multidomain scaffold that integrates regulatory and catalytic elements, with the N-terminal domains providing interaction platforms and the C-terminal regions housing enzymatic cores. Key structural features include the catalytic core composed of the ROC-COR-kinase triad, which assembles to form the and enables coordinated enzymatic regulation. Cryo-electron microscopy (cryo-EM) structures of full-length human LRRK2 reveal a compact, J-shaped approximately 225 in length, with flexible N-terminal regions and tight interdomain contacts that maintain a folded state. As of 2025, additional cryo-EM analysis of the full-length monomeric LRRK2 in complex with a 14-3-3 dimer has elucidated how at key sites stabilizes autoinhibition through specific interdomain interactions. These structures also highlight the protein's potential for higher-order assembly, including filament-like formations mediated by ROC-COR interactions, particularly in contexts involving association. Recent cryo-electron tomography (cryo-ET) studies confirm that full-length LRRK2 oligomerizes on in its autoinhibited state, with both wild-type and Parkinson's disease-linked variants exhibiting this behavior. Post-translational modifications play a critical role in modulating LRRK2's architecture and activity, including at sites such as Ser910 and Ser935 within the region between the ANK and LRR domains, which influence and 14-3-3 binding. A 2025 cryo-EM structure of the LRRK2-14-3-3 complex reveals that these events promote 14-3-3 binding to maintain the autoinhibited conformation by bridging regulatory domains. Additional modifications encompass ubiquitination, primarily at residues in the and WD40 domains, which regulates protein stability and degradation via E3 ligases like TRIM1; and events at other sites like Thr1343 near the ROC domain. Dimerization interfaces, including those in the COR and WD40 domains, are further influenced by these modifications to control oligomeric states.

Biological Functions

Enzymatic Activities

LRRK2 functions as a dual-enzyme protein with serine/ and ROCO family activities, both integral to its regulatory mechanisms. The activity enables autophosphorylation at multiple sites, including residues in the ROC domain such as Thr1343 and Thr1491, which influence overall protein conformation and activity. at Ser935, located between the LRR and ROC domains, is mediated by other but serves as a for LRRK2 activity. Additionally, LRRK2 phosphorylates a subset of Rab , such as Rab10, at conserved residues in their switch II motifs—exemplified by Thr73 in Rab10—thereby modulating Rab effector interactions and trafficking processes. The catalytic mechanism relies on ATP binding to the bilobal domain, where the N-lobe facilitates positioning and the C-lobe coordinates substrate alignment for transfer. Complementing its kinase function, LRRK2's activity is centered in the ROC domain, which binds GTP and catalyzes its to GDP through conserved G motifs, including the P-loop for coordination and other elements for . The contiguous COR domain enhances this GTPase efficiency by stabilizing the ROC conformation and facilitating dimerization, which is necessary for optimal hydrolysis rates. This GTPase cycle drives nucleotide-dependent conformational shifts in LRRK2, transitioning between compact GDP-bound and extended GTP-bound states that propagate regulatory signals across the protein. Inter-domain regulation tightly couples these enzymatic activities, with GTP binding to the ROC domain allosterically activating the distal domain through the intervening COR segment, forming a functional ROC-COR- core that amplifies output. In contrast, GDP binding or impaired correlates with reduced kinase potency, underscoring a bidirectional feedback loop where kinase-mediated autophosphorylation in the ROC domain can further modulate kinetics. These activities are quantified using established assays: kinase function is evaluated via radioactive transfer from [γ-³²P]ATP to synthetic peptides or full-length substrates like Rab10, monitoring incorporation by scintillation counting or phospho-specific antibodies. GTPase activity employs colorimetric or HPLC-based detection of inorganic release from GTP, yielding rates with Michaelis-Menten parameters such as Km values for GTP of approximately 400 μM for full-length LRRK2.

Cellular Roles

LRRK2 plays a central role in regulating vesicle trafficking by a subset of Rab GTPases, such as Rab8, Rab10, and Rab35, at a conserved residue in their switch II domain, which modulates their interactions with effector proteins and influences endosomal-lysosomal sorting. This facilitates the of LRRK2 to cellular and coordinates the movement of vesicles along cytoskeletal tracks, supporting processes like endocytic and trans-Golgi network organization. In neurons, LRRK2-mediated Rab promotes neurite outgrowth by enhancing the delivery of components to growth cones and maintains synaptic function through the regulation of vesicle and at presynaptic terminals. LRRK2 also regulates ciliogenesis by phosphorylating Rab GTPases such as Rab10 and Rab12, which suppresses primary cilia formation and maintains integrity, with implications for cellular signaling pathways like . In the autophagy-lysosome pathway, LRRK2 modulates macroautophagy initiation by interacting with Beclin-1, promoting the assembly of the initiation complex in a kinase-dependent manner that is independent of signaling. It also influences formation and maturation by regulating lysosomal pH and calcium , ensuring efficient fusion with lysosomes for cargo degradation. LRRK2 interacts with VPS35, a component of the retromer complex, to facilitate endosome-to-Golgi retrieval of autophagy-related proteins, thereby supporting the recycling of essential components for sustained autophagic flux under physiological conditions. LRRK2 contributes to cytoskeletal dynamics through direct association with microtubules, binding to β-tubulin via its ROC domain and phosphorylating it at Thr107 to promote polymerization and stabilization. This interaction helps maintain microtubule integrity, which is crucial for intracellular transport and organelle positioning in neurons. In neuronal cells, LRRK2 influences morphology by regulating actin dynamics at filopodia and lamellipodia, supporting dendrite and axon extension during development. Additionally, LRRK2 modulates immune cell migration by linking Rab-mediated vesicle trafficking to actin remodeling in macrophages and neutrophils, facilitating directed movement toward inflammatory cues. In immune cells, LRRK2 regulates cytokine production by enhancing NF-κB and MAPK signaling pathways in response to microbial stimuli, leading to the secretion of pro-inflammatory cytokines such as TNF-α and IL-1β in macrophages. It also supports phagocytosis by recruiting to maturing phagosomes via Rab5 and Rab10 phosphorylation, promoting efficient particle uptake and lysosomal degradation in both macrophages and neutrophils. Beyond immune functions, LRRK2 is expressed in kidney podocytes, where it maintains lysosomal homeostasis and supports glomerular filtration by regulating endocytic trafficking and protein reabsorption in proximal tubules. LRRK2 participates in mitochondrial quality control by modulating basal mitophagy through Rab10 and Rab12 phosphorylation, which facilitates the delivery of damaged mitochondria to lysosomes for selective degradation. This process ensures mitochondrial homeostasis without involving apoptosis under normal physiological conditions.

Genetics and Mutations

Pathogenic Variants

Pathogenic variants in the LRRK2 gene are primarily missense mutations that lead to altered protein function, with most classified as gain-of-function changes contributing to Parkinson's disease pathogenesis. These variants cluster in key functional domains of the LRRK2 protein, including the kinase, ROC, and COR domains, and are identified through genetic screening in familial and sporadic cases. Among the most common pathogenic variants is G2019S, located in the domain, which accounts for a significant proportion of LRRK2-associated in specific populations such as Ashkenazi Jewish and North African descent. Other frequently reported variants include R1441C, R1441G, and R1441H in the ROC domain, as well as I2020T in the domain and Y1699C in the COR domain. These mutations are recurrent across diverse ethnic groups and have been confirmed through multiple pedigree analyses.62971-0/fulltext) Rare variants include risk alleles such as G2385R in the domain, particularly prevalent in Asian cohorts, which confers increased susceptibility to . Loss-of-function variants, such as frameshift mutations, occur at low frequencies and are not associated with increased risk, with evidence suggesting they may be neutral or tolerated in human populations. At the molecular level, most pathogenic variants exhibit gain-of-function effects; for instance, G2019S increases LRRK2 activity by 2- to 3-fold compared to wild-type, as measured by autophosphorylation and substrate assays. Similarly, I2020T enhances activity, while R1441C/G/H mutations impair GTP hydrolysis in the ROC domain, leading to prolonged GTP-bound states and indirect hyperactivation. The Y1699C variant in the COR domain disrupts the cycle, further contributing to dysregulated enzymatic function. In contrast, loss-of-function variants reduce protein levels without evident pathological consequences. Pathogenic LRRK2 variants are classified as pathogenic or likely pathogenic according to American College of and (ACMG) criteria, based on functional studies, segregation data, and population frequencies. Penetrance varies by variant and ancestry; for G2019S, lifetime risk estimates range from 20% to 80%, with age-dependent expression rising to over 70% by age 80 in high-risk groups.

Inheritance Patterns and Prevalence

Mutations in the LRRK2 gene are primarily inherited in an autosomal dominant pattern, meaning that a single copy of a pathogenic variant from one parent is sufficient to increase the risk of developing (PD). However, is incomplete and age-dependent, with estimates ranging from 17% to 85% by age 80 years, varying by specific variant and population. Rare cases of recessive inheritance have been reported, particularly in homozygous carriers of variants like G2019S, though these are exceptional and do not alter the predominant dominant mode. Worldwide, LRRK2 pathogenic variants account for approximately 1-2% of sporadic PD cases and 3-5% of familial PD cases, making them the most common genetic cause of PD overall. Prevalence is notably higher in certain ethnic groups due to founder effects; for instance, up to 40% of familial PD cases in the Basque population and around 30% in Arab-Berber populations are attributed to LRRK2 mutations, primarily G2019S or R1441G. The G2019S variant, in particular, exhibits a strong in populations of Middle Eastern, North African, and Ashkenazi Jewish descent, where it shares a common originating from a single ancestral event.62924-3) Screening data from large cohorts, such as the Parkinson's Progression Markers Initiative (PPMI), confirm these patterns, identifying LRRK2 variants in about 1-2% of early-onset or prodromal PD participants, with higher rates in at-risk families. of LRRK2 mutations is further modulated by genetic modifiers, including interactions with variants in other PD-associated genes like GBA, which can accelerate disease progression or alter risk in compound carriers.

Role in Disease

Pathophysiology in Parkinson's Disease

Mutations in LRRK2, particularly those that enhance its kinase activity like G2019S, drive the selective degeneration of neurons in the , a core feature of (PD) pathology. This hyperactivation promotes excessive of Rab GTPases, such as Rab8A, Rab10, and Rab35, which disrupts vesicular trafficking and endolysosomal function, thereby impairing the autophagic clearance of aggregates. As a result, accumulates intracellularly, exacerbating proteotoxic stress and contributing to neuronal loss. LRRK2 dysfunction also perturbs mitochondrial , a critical in neurons. Pathogenic mutations inhibit /Parkin-dependent mitophagy, preventing the selective removal of damaged mitochondria and leading to their accumulation, heightened , and increased mitochondrial fission. This mitochondrial impairment amplifies energy deficits and production, further promoting neuronal in PD. Neuroinflammation represents another key mechanism linking LRRK2 to PD progression. LRRK2 is highly expressed in , where mutations like G2019S shift these cells toward a pro-inflammatory state, enhancing the release of cytokines such as TNF-α, IL-1β, and IL-6. This microglial activation fosters a neurotoxic environment, while LRRK2 in peripheral immune cells, including monocytes, may propagate that infiltrates the , worsening dopaminergic damage. In addition to , mutant LRRK2 facilitates broader , including the assembly of Lewy bodies—the pathological hallmark of PD—and even tau inclusions in some cases. Mutant LRRK2 co-localizes with in Lewy bodies and promotes the and fibrillization of at serine 129, accelerating aggregate formation. Knock-in models harboring the G2019S mutation provide direct evidence of LRRK2's role in PD-like pathology, exhibiting striatal dysregulation, overload, and mitochondrial abnormalities by 12-20 months of age, often without substantial neuron loss. These models highlight how endogenous levels of mutant LRRK2 suffice to induce subtle, age-dependent pathological changes mirroring early PD.

Associations with Other Conditions

Beyond its role in Parkinson's disease, LRRK2 variants exhibit pleiotropic effects on susceptibility to other conditions, including protective associations. Common loss-of-function or deactivating variants, such as N551K and R1398H, reduce the risk of by enhancing activity and dampening excessive inflammatory responses in immune cells. These same variants also confer protection against by modulating antimicrobial immunity and reducing bacterial persistence in macrophages, thereby lowering disease incidence in carriers. Similarly, heterozygous loss-of-function truncations in LRRK2 lead to reduced protein levels without strongly associating with pathology, suggesting a lower incidence of the disorder in such carriers compared to gain-of-function holders. LRRK2 has potential links to other neurodegenerative disorders through interactions with pathology. In mutation carriers, tau aggregates resembling Alzheimer's disease-type neurofibrillary tangles are prominent, present in 100% of cases examined and abundant in 91%, often co-occurring with amyloid-beta deposits and correlating with symptoms. As of 2025, cellular models demonstrate that the G2019S exacerbates tau and seeding, further supporting shared mechanisms with tauopathies. Additionally, the G2019S variant has been identified in families with , where carriers display atypical parkinsonian features alongside LRRK2-related neuropathology, highlighting shared tau-mediated mechanisms. Non-neurological associations include immune-mediated disorders and organ dysfunction. LRRK2 variants contribute to , particularly , via dysregulation of innate immunity, such as altered function and heightened interferon-gamma responses in monocytes, increasing susceptibility in carriers. Gain-of-function mutations like G2019S exacerbate kidney injury by promoting mitochondrial fission through MFN2 degradation, leading to renal tubular damage and suggesting elevated risk of dysfunction, including potential membranous nephropathy in affected individuals. Cancer associations with LRRK2 are mixed, reflecting context-dependent tumor suppressor or oncogenic roles. G2019S carriers show increased risk for non-skin cancers, including , colon, and hematologic malignancies, potentially due to enhanced kinase-driven proliferation. Conversely, LRRK2 loss promotes carcinogen-induced tumorigenesis in models, with animals developing more and larger adenomas, indicating a protective suppressor function in lung adenocarcinoma. Some epidemiological data suggest a reduced risk in broader Parkinson's cohorts, though LRRK2-specific effects remain debated with reports of elevated incidence in mutation carriers. Emerging evidence points to LRRK2's involvement in through regulation of lung . LRRK2 deficiency in mice worsens bleomycin-induced fibrosis by impairing in alveolar type II cells, accelerating , and recruiting profibrotic macrophages via CCL2 signaling, underscoring its protective role against fibroblast-mediated scarring. LRRK2's ubiquitous expression in immune and tissues further supports its broad pleiotropic impact across inflammatory and fibrotic conditions.

Therapeutics and Research Directions

Kinase Inhibition Strategies

Kinase inhibition represents a primary therapeutic strategy for modulating LRRK2 activity, particularly in the context of gain-of-function mutations that enhance its hyperactivity in . These approaches focus on small-molecule inhibitors that target the kinase domain to reduce pathological of downstream substrates, thereby mitigating neuronal dysfunction without altering the protein's expression levels. Type I inhibitors, such as GSK2578215A, are ATP-competitive agents that bind to the active conformation of the LRRK2 domain, demonstrating potent inhibition with IC50 values of approximately 9-10 nM against both wild-type and G2019S mutant forms. This class stabilizes the DFG-in (Asp-Phe-Gly-in) active state, effectively competing with ATP to block substrate access and has shown utility in early preclinical models for assessing LRRK2-dependent signaling. In contrast, Type II inhibitors like MLi-2 adopt an allosteric mechanism, binding adjacent to the ATP site to induce and lock the kinase in an inactive DFG-out conformation, which enhances selectivity by avoiding competition with cellular ATP levels and minimizing off-target kinase inhibition. MLi-2 exhibits high potency (IC50 < 2 nM), exceptional kinome selectivity (over 200 kinases tested), and favorable brain penetration in rodent models, making it a preferred tool compound for central nervous system applications. Preclinical studies have demonstrated the efficacy of these inhibitors in reducing LRRK2-mediated of Rab10 at 73 (pT73-Rab10) in mutant LRRK2-expressing cellular and animal models, thereby restoring lysosomal and endocytic trafficking defects associated with disease pathology. Furthermore, treatment with selective inhibitors like MLi-2 has provided in (iPSC)-derived neurons harboring G2019S mutations, rescuing mitochondrial dysfunction and promoting survival under stress conditions. Despite these advances, key challenges persist in developing clinically viable LRRK2 inhibitors, including achieving sufficient blood-brain barrier penetration to reach therapeutic concentrations in the while avoiding excessive peripheral exposure. Peripheral inhibition has raised concerns for off-target effects, such as and immune cell toxicity observed in models of chronic LRRK2 suppression, which mimic phenotypes seen in LRRK2 animals, including alveolar type II cell . To address these hurdles and monitor target engagement, biomarker development has centered on peripheral measures of kinase inhibition, with pT73-Rab10 in serum and phospho-Ser935-LRRK2 (pS935) in peripheral mononuclear cells serving as robust pharmacodynamic markers that correlate with central inhibition in preclinical and early studies. These assays enable dose-response assessment and stratification by quantifying reductions in substrate following inhibitor administration.

Ongoing Clinical Trials and Challenges

Ongoing clinical trials for LRRK2-targeted therapies primarily focus on inhibition as a disease-modifying strategy for (PD), with several candidates advancing to human studies. Phase I and II trials have evaluated oral LRRK2 inhibitors such as BIIB122, developed by in collaboration with Therapeutics, demonstrating safety and tolerability in healthy participants and PD patients with LRRK2 mutations. Safety data from these trials indicate dose-dependent inhibition of phosphorylated Rab proteins (pRab), a key of LRRK2 activity, achieving up to 90% reduction at higher doses without significant adverse events. Similarly, DNL151, the precursor compound to BIIB122 from , showed comparable pharmacodynamic effects in early-phase studies, supporting its progression to the phase 2a trial initiated in late 2024, which assesses safety, pRab modulation, and early efficacy signals in LRRK2-associated PD. As of November 2025, the trial remains ongoing, with estimated completion in February 2028. Other candidates include ARV-102, which completed Phase 1 in April 2025 showing dose-dependent LRRK2 degradation and favorable safety, supporting advancement to further studies in LRRK2-linked PD. Additionally, Neuron23 initiated a Phase 2 trial of its LRRK2 inhibitor in early in early 2025. Biomarker-driven approaches are enriching trial cohorts through initiatives like the Parkinson's Progression Markers Initiative (PPMI), which prioritizes G2019S mutation carriers to track prodromal changes. In PPMI-enriched studies, endpoints incorporate dopamine transporter (DaTscan) imaging to quantify striatal dopamine loss and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores to measure motor and non-motor progression, enabling sensitive detection of therapeutic impacts in at-risk individuals. Gene therapy strategies are emerging in preclinical models, with (AAV)-delivered (shRNA) demonstrating effective LRRK2 silencing in non-human primates, reducing activity and associated pathology without overt toxicity. Despite these advances, clinical development faces significant challenges, including the incomplete of LRRK2 mutations, which necessitates large cohort sizes to achieve statistical power for detecting modest elevations. The protracted course of PD further delays efficacy readouts, often requiring years-long follow-up to observe changes in progression markers. Ethical concerns also arise in trials involving carriers, balancing potential benefits against risks of psychological distress from genetic disclosure and intervention in pre-symptomatic stages. As of October 2025, the Rallying to the Challenge conference highlighted progress in LRRK2 inhibition clinical trials, including updates on Therapeutics' Phase 2 and LUMA studies. Additionally, exploratory research points to potential synergies between LRRK2 inhibitors and alpha-synuclein-targeted therapies, such as aggregation inhibitors, to address overlapping pathways in PD pathogenesis.

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