title: Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats.
abstract: Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can cause late-onset Parkinson disease. Past studies have provided conflicting evidence for the protective effects of LRRK2 knockdown in models of Parkinson disease as well as other disorders. These discrepancies may be caused by uncertainty in the pathobiological mechanisms of LRRK2 action. Previously, we found that LRRK2 knockdown inhibited proinflammatory responses from cultured microglia cells. Here, we report LRRK2 knockout rats as resistant to dopaminergic neurodegeneration elicited by intracranial administration of LPS. Such resistance to dopaminergic neurodegeneration correlated with reduced proinflammatory myeloid cells recruited in the brain. Additionally, adeno-associated virus-mediated transduction of human α-synuclein also resulted in dopaminergic neurodegeneration in wild-type rats. In contrast, LRRK2 knockout animals had no significant loss of neurons and had reduced numbers of activated myeloid cells in the substantia nigra. Although LRRK2 expression in the wild-type rat midbrain remained undetected under nonpathological conditions, LRRK2 became highly expressed in inducible nitric oxide synthase (iNOS)-positive myeloid cells in the substantia nigra in response to α-synuclein overexpression or LPS exposures. Our data suggest that knocking down LRRK2 may protect from overt cell loss by inhibiting the recruitment of chronically activated proinflammatory myeloid cells. These results may provide value in the translation of LRRK2-targeting therapeutics to conditions where neuroinflammation may underlie aspects of neuronal dysfunction and degeneration.
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: João P L
authors.initials: JP
authors.lastname: Daher
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Volpicelli-Daley
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Blackburn
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Moehle
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294 abwest@uab.edu.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: West
mesh_terms: D000818:Animals; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008070:Lipopolysaccharides / Q000633:toxicity; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D055647:Rats, Transgenic; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D008070:Lipopolysaccharides; D051844:alpha-Synuclein; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C547428:LRRK2 protein, rat; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: CD68; NACP; PARK8; SNCA; rat knockout