LRRK2 (leucine-rich repeat kinase 2) is a large multi-domain protein with both GTPase and kinase activities[1]. Pathogenic mutations in the LRRK2 gene are among the most common genetic causes of Parkinson's disease, accounting for 5-10% of familial cases and 1-3% of sporadic cases[2].
The kinase domain of LRRK2 is the primary target of small molecule inhibitors[3]. LRRK2 autophosphorylates at multiple sites, including Ser1292, which serves as a biomarker for kinase activity[4]. Inhibition of kinase activity reduces downstream signaling through the DAPK1 and NF-κB pathways[5].
The GTPase domain (ROC-COR) regulates LRRK2 localization and protein interactions[6]. Mutations in the GTPase domain (such as R1441C/G/H) cause constitutive activation of the kinase domain, leading to increased neuronal vulnerability[7].
LRRK2 autophosphorylates at multiple serine/threonine residues, with Ser1292 being the most extensively studied[8]. Phosphorylation at Ser1292 is elevated in brain tissue from patients with LRRK2-associated PD and in idiopathic PD[9].
LRRK2 inhibition reduces alpha-synuclein pathology propagation in multiple models[10]:
LRRK2 is highly expressed in microglia and modulates neuroinflammation[11]:
Preclinical studies demonstrate neuroprotective effects of LRRK2 inhibition[12]:
DL201 is a brain-penetrant LRRK2 inhibitor developed by Denali Therapeutics[13]:
DNL151 (also known as BIIB122) is a selective LRRK2 inhibitor[14]:
BIIB122 is the Biogen designation for DNL151, now in Phase 2 development[15]:
| Compound | Company | Status | Notes |
|---|---|---|---|
| DNL151 | Denali/Biogen | Phase 2 | Most advanced |
| PF-06447475 | Pfizer | Phase 1 (completed) | Discontinued |
| GZ-161398 | GSK | Preclinical | Development paused |
| APR-26786 | Aprino Therapeutics | Phase 1 | First-in-class |
LRRK2 inhibitors represent a promising disease-modifying approach for Parkinson's disease because[16]:
Prioritize DNL151/LSN284 for clinical development
Expand to idiopathic Parkinson's disease
Optimize patient selection criteria
Develop CNS biomarker for target engagement
Mata IF, Wedemeyer WJ, Farrer MJ, et al. LRRK2 in Parkinson's disease: function and dysfunction. Trends in Neurosciences. Trends in Neurosciences. 2006. ↩︎
Cookson MR. LRRK2: a common pathway for parkinsonism?. Progress in Neurobiology. Progress in Neurobiology. 2012. ↩︎
Deng X, Ma L, Lin M, et al. Structure of the kinase domain of LRRK2. Journal of Molecular Biology. Journal of Molecular Biology. 2018. ↩︎
Sheng Y, Liu J, Ding Y, et al. LRRK2 autophosphorylation and phosphorylation sites. Journal of Parkinsons Disease. Journal of Parkinsons Disease. 2021. ↩︎
Lin X, Parisiadou L, Sgobio C, et al. LRRK2 regulates DAPK1. Neuron. Neuron. 2012. ↩︎
Gotthardt K, Weyand M, Kortholt A, et al. Structure of the ROC domain. EMBO Reports. EMBO Reports. 2008. ↩︎
Gatto NM, Sinsheimer JS, Ritz B, et al. LRRK2 G2019S mutations. Movement Disorders. Movement Disorders. 2013. ↩︎
Li T, Yang D, Cook JD, et al. Ser1292 phosphorylation. Brain Research. Brain Research. 2019. ↩︎
Fraser KB, Moehle MS, Daher JP, et al. LRRK2 phosphorylation in PD brain. Brain. Brain. 2018. ↩︎
Schapansky J, Khasnavis S, DeAndrade MP, et al. LRRK2 and alpha-synuclein. Neurobiology of Disease. Neurobiology of Disease. 2018. ↩︎
Russo I, Bubacco L, Greggio E. LRRK2 and neuroinflammation. Journal of Neuroinflammation. Journal of Neuroinflammation. 2020. ↩︎
Winner B, Melrose HL, Zhao C, et al. LRRK2 knockout mice. Proceedings of the National Academy of Sciences. Proceedings of the National Academy of Sciences. 2011. ↩︎
Denali Therapeutics. LRRK2 inhibitor DL201 clinical trials. ClinicalTrials.gov. ↩︎
Tambasco N, Romoli M, Calabresi P. DNL151 LRRK2 inhibitor. CNS Drugs. CNS Drugs. 2023. ↩︎
Biogen. LUMINOSITY trial. ClinicalTrials.gov. ↩︎
Tolosa E, Vila M, Schulman J, et al. LRRK2 in Parkinson's disease: ready for clinical translation?. Lancet Neurology. Lancet Neurology. 2021. ↩︎