title: Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration.
abstract: Therapeutic approaches to slow or block the progression of Parkinson disease (PD) do not exist. Genetic and biochemical studies implicate α-synuclein and leucine-rich repeat kinase 2 (LRRK2) in late-onset PD. LRRK2 kinase activity has been linked to neurodegenerative pathways. However, the therapeutic potential of LRRK2 kinase inhibitors is not clear because significant toxicities have been associated with one class of LRRK2 kinase inhibitors. Furthermore, LRRK2 kinase inhibitors have not been tested previously for efficacy in models of α-synuclein-induced neurodegeneration. To better understand the therapeutic potential of LRRK2 kinase inhibition in PD, we evaluated the tolerability and efficacy of a LRRK2 kinase inhibitor, PF-06447475, in preventing α-synuclein-induced neurodegeneration in rats. Both wild-type rats as well as transgenic G2019S-LRRK2 rats were injected intracranially with adeno-associated viral vectors expressing human α-synuclein in the substantia nigra. Rats were treated with PF-06447475 or a control compound for 4 weeks post-viral transduction. We found that rats expressing G2019S-LRRK2 have exacerbated dopaminergic neurodegeneration and inflammation in response to the overexpression of α-synuclein. Both neurodegeneration and neuroinflammation associated with G2019S-LRRK2 expression were mitigated by LRRK2 kinase inhibition. Furthermore, PF-06447475 provided neuroprotection in wild-type rats. We could not detect adverse pathological indications in the lung, kidney, or liver of rats treated with PF-06447475. These results demonstrate that pharmacological inhibition of LRRK2 is well tolerated for a 4-week period of time in rats and can counteract dopaminergic neurodegeneration caused by acute α-synuclein overexpression.
authors.affiliation: From the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: João P L
authors.initials: JP
authors.lastname: Daher
authors.affiliation: From the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Hisham A
authors.initials: HA
authors.lastname: Abdelmotilib
authors.affiliation: From the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Xianzhen
authors.initials: X
authors.lastname: Hu
authors.affiliation: From the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Volpicelli-Daley
authors.affiliation: From the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Moehle
authors.affiliation: From the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Kyle B
authors.initials: KB
authors.lastname: Fraser
authors.affiliation: the Pfizer Neuroscience Research Unit, Cambridge, Massachusetts.
authors.forename: Elie
authors.initials: E
authors.lastname: Needle
authors.affiliation: the Pfizer Neuroscience Research Unit, Cambridge, Massachusetts.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Pfizer Pharmacokinetics, Dynamics, and Metabolism Cambridge, Cambridge, Massachusetts 02139, and.
authors.forename: Stefanus J
authors.initials: SJ
authors.lastname: Steyn
authors.affiliation: Pfizer Worldwide Medicinal Chemistry, Cambridge, Massachusetts 02139.
authors.forename: Paul
authors.initials: P
authors.lastname: Galatsis
authors.affiliation: the Pfizer Neuroscience Research Unit, Cambridge, Massachusetts.
authors.forename: Warren D
authors.initials: WD
authors.lastname: Hirst
authors.affiliation: From the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, abwest@uab.edu.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: West
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D007276:Injections, Intraventricular; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: C000597233:3-(4-(morpholin-4-yl)-7H-pyrrolo(2,3-d)pyrimidin-5-yl)benzonitrile; D000978:Antiparkinson Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D051844:alpha-Synuclein; C547428:LRRK2 protein, rat; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: dopamine; kinase inhibitors; leucine-rich repeat kinase 2 (LRRK2); neurodegenerative disease; neuroinflammation; neurorestoration; α-synuclein (α-synuclein)