Leucine-rich repeat kinase 2 (LRRK2) is an important target in the treatment of Parkinson’s disease (PD). In addition to being over-expressed in neurons, LRRK2 mutations are found in patients with late-onset PD, and believed to be a common cause. One such mutation related to onset of PD is Glutamine 2019 to serine. This mutation increases the kinase activity of LRRK2, which in turn increases neurodegeneration.
Knockdown of LRRK2 has been shown to modify synaptogenesis, resulting in mutated synapses compared to normal mice neurons. But, knockdown of LRRK2 in rats also resulted in loss of neuroinflammation due to reduced expression of a-synuclein. This expression was demonstrated in LRRK2 knockout mice in vivo.
Inhibiting LRRK2 activity with small molecules is a potential target for the treatment of PD. The inhibitor PF-06447475 is a small molecule inhibitor that inhibits LRRK2 kinase activity. PF-06447475 acts in both wild type and G2019S mutated LRRK2. It inhibits neurodegeneration caused by the overexpression of a-synuclein PF-06447475 also demonstrates an ability to cross the blood-brain barrier. It is well tolerated, with rats showing no toxicities after 4 weeks dosing in animal trials.
LRRK2 inhibitors available from LKT Laboratories include:
References:
Parisiadou, L., Yu, J. Sgobio C. et al. “LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity” Nat. Neurosci. 2014 March; 17(3): 367-376. Doi: 10.1038/nn.3636.
Daher, J.P.L., Volpicelli-Daley, L.A., Blackburn, J.P., et al. “Abrogation of alpha-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficiaent rats” Proc. Nat. Acad. Sci. 2014, June. 111(25): 9289-9294. Doi: 10.1073/pnas.1403215111.
Daher, J.P.L., Abdelmotilib, H.A., Hu, X., et al. “Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates alpha-Synuclein Gene-induced Neurodegeneration” J. Biol. Chem. 2015 August. 290(32): 19433-19444. Doi: 10.1074/jbc.M115.660001.