title: Leucine-rich repeat kinase 2 modulates neuroinflammation and neurotoxicity in models of human immunodeficiency virus 1-associated neurocognitive disorders.
abstract: Leucine-rich repeat kinase 2 (LRRK2) is the single most common genetic cause of both familial and sporadic Parkinson's disease (PD), both of which share pathogenetic and neurologic similarities with human immunodeficiency virus 1 (HIV-1)-associated neurocognitive disorders (HAND). Pathologic LRRK2 activity may also contribute to neuroinflammation, because microglia lacking LRRK2 exposed to proinflammatory stimuli have attenuated responses. Because microglial activation is a hallmark of HIV-1 neuropathology, we have investigated the role of LRRK2 activation using in vitro and in vivo models of HAND. We hypothesize that LRRK2 is a key modulator of microglial inflammatory responses, which play a pathogenic role in both HAND and PD, and that these responses may cause or exacerbate neuronal damage in these diseases. The HIV-1 Tat protein is a potent neurotoxin produced during HAND that induces activation of primary microglia in culture and long-lasting neuroinflammation and neurotoxicity when injected into the CNS of mice. We found that LRRK2 inhibition attenuates Tat-induced pS935-LRRK2 expression, proinflammatory cytokine and chemokine expression, and phosphorylated p38 and Jun N-terminal kinase signaling in primary microglia. In our murine model, cortical Tat injection in LRRK2 knock-out (KO) mice results in significantly diminished neuronal damage, as assessed by microtubule-associated protein 2 (MAP2), class III β-tubulin TUJ1, synapsin-1, VGluT, and cleaved caspase-3 immunostaining. Furthermore, Tat-injected LRRK2 KO animals have decreased infiltration of peripheral neutrophils, and the morphology of microglia from these mice were similar to that of vehicle-injected controls. We conclude that pathologic activation of LRRK2 regulates a significant component of the neuroinflammation associated with HAND.
authors.affiliation: Center for Neural Development and Disease and jenna_puccini@urmc.rochester.edu.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Puccini
authors.affiliation: Center for Neural Development and Disease and.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Marker
authors.affiliation: Graduate Program in Medical Illustration, Rochester Institute of Technology, Rochester, New York 14623.
authors.forename: Tim
authors.initials: T
authors.lastname: Fitzgerald
authors.affiliation: Center for Neural Development and Disease and.
authors.forename: Justin
authors.initials: J
authors.lastname: Barbieri
authors.affiliation: Center for Neural Development and Disease and.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Kim
authors.affiliation: Center for Neural Development and Disease and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Miller-Rhodes
authors.affiliation: Center for Neural Development and Disease and.
authors.forename: Shao-Ming
authors.initials: SM
authors.lastname: Lu
authors.affiliation: Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642, and.
authors.forename: Stephen
authors.initials: S
authors.lastname: Dewhurst
authors.affiliation: Center for Neural Development and Disease and.
authors.forename: Harris A
authors.initials: HA
authors.lastname: Gelbard
mesh_terms: D015526:AIDS Dementia Complex / Q000150:complications / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects; D003072:Cognition Disorders / Q000150:complications / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D015696:Gene Products, tat / Q000008:administration & dosage / Q000633:toxicity; D015658:HIV Infections / Q000150:complications / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008845:Microinjections; D009410:Nerve Degeneration / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D015696:Gene Products, tat; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: HIV-1; LRRK2; Parkinson's disease; microglia; neuroinflammation; neurotoxicity
references.citation: J Neuropathol Exp Neurol. 1998 Jun;57(6):563-70
references.pmid: 9630236
references.citation: Nat Chem Biol. 2011 Apr;7(4):203-5
references.pmid: 21378983
references.citation: J Neuroimmunol. 2008 Aug 30;200(1-2):100-10
references.pmid: 18653246
references.citation: J Neurovirol. 2012 Oct;18(5):341-53
references.pmid: 22811265
references.citation: Ann Neurol. 1992 Apr;31(4):349-60
references.pmid: 1586135
references.citation: J Neurosci Res. 2009 May 1;87(6):1283-95
references.pmid: 19025767
references.citation: J Proteome Res. 2010 Apr 5;9(4):1738-45
references.pmid: 20108944
references.citation: J Neurosci Res. 1992 Apr;31(4):616-21
references.pmid: 1578513
references.citation: J Neurochem. 2008 Oct;107(2):557-69
references.pmid: 18717813
references.citation: J Neurosci. 2013 Jun 12;33(24):9998-10010
references.pmid: 23761895
references.citation: Am J Pathol. 1990 May;136(5):1085-92
references.pmid: 1693470
references.citation: BMB Rep. 2010 Apr;43(4):233-44
references.pmid: 20423607
references.citation: J Neuroinflammation. 2012;9:261
references.pmid: 23190742
references.citation: PLoS One. 2011;6(3):e17153
references.pmid: 21390248
references.citation: Nat Protoc. 2006;1(3):1287-96
references.pmid: 17406413
references.citation: Neuron. 2006 Nov 22;52(4):587-93
references.pmid: 17114044
references.citation: Biochem J. 2010 Sep 15;430(3):393-404
references.pmid: 20642453
references.citation: Mol Neurodegener. 2012;7:25
references.pmid: 22647713
references.citation: J Neuroinflammation. 2012;9:115
references.pmid: 22651808
references.citation: Neurobiol Dis. 2011 Mar;41(3):706-16
references.pmid: 21168496
references.citation: Neuropathology. 2009 Aug;29(4):433-42
references.pmid: 19170891
references.citation: Hum Mol Genet. 2007 Jan 15;16(2):223-32
references.pmid: 17200152
references.citation: J Vis Exp. 2010;(43). pii: 2059. doi: 10.3791/2059
references.pmid: 20972389
references.citation: Science. 2005 May 27;308(5726):1314-8
references.pmid: 15831717
references.citation: J Neurochem. 2009 May;109(4):959-68
references.pmid: 19302196
references.citation: Nature. 2011 Apr 21;472(7343):319-24
references.pmid: 21389984
references.citation: Neuroscience. 2006;139(3):791-4
references.pmid: 16504409
references.citation: Neurobiol Dis. 2007 Jun;26(3):661-70
references.pmid: 17451964
references.citation: J Immunol. 2006 Jul 1;177(1):702-11
references.pmid: 16785569
references.citation: J Neurosci. 2012 Feb 1;32(5):1602-11
references.pmid: 22302802
references.citation: J Acquir Immune Defic Syndr. 2002 Oct 1;31 Suppl 2:S43-54
references.pmid: 12394782
references.citation: Trends Biochem Sci. 2012 Aug;37(8):325-32
references.pmid: 22682109
references.citation: J Immunol. 2012 Jul 1;189(1):381-92
references.pmid: 22661091
references.citation: Biochem J. 2010 Sep 15;430(3):405-13
references.pmid: 20659021
references.citation: J Neuroinflammation. 2012;9:94
references.pmid: 22594666
references.citation: Commun Integr Biol. 2013 Nov 1;6(6):e27670
references.pmid: 24563721
references.citation: S Afr Med J. 2013 Oct;103(10):758-62
references.pmid: 24079630
references.citation: J Biol Chem. 2014 Nov 21;289(47):32937-51
references.pmid: 25228699
references.citation: J Neurovirol. 2013 Apr;19(2):144-9
references.pmid: 23389619
references.citation: Neurology. 2010 Dec 7;75(23):2087-96
references.pmid: 21135382
references.citation: J Neuroimmunol. 1999 Feb 1;94(1-2):28-39
references.pmid: 10376933
references.citation: Immunogenetics. 1983;18(3):229-39
references.pmid: 6618532
references.citation: Nat Rev Neurosci. 2007 Jan;8(1):33-44
references.pmid: 17180161
references.citation: ALTEX. 2009;26(2):83-94
references.pmid: 19565166
references.citation: J Histochem Cytochem. 1974 Dec;22(12):1077-83
references.pmid: 4374474
references.citation: Front Cell Neurosci. 2013 Mar 18;7:26
references.pmid: 23507975
references.citation: J Neurochem. 2014 Feb;128(4):561-76
references.pmid: 24117733
references.citation: PLoS One. 2011;6(9):e23915
references.pmid: 21912650
references.citation: Neuron. 2004 Nov 18;44(4):601-7
references.pmid: 15541309
references.citation: Crit Rev Neurobiol. 1996;10(1):57-67
references.pmid: 8853954
references.citation: J Int AIDS Soc. 2013;16:18506
references.pmid: 23883539
references.citation: PLoS One. 2012;7(4):e34693
references.pmid: 22496842
references.citation: J Neurosci. 2011 Nov 9;31(45):16064-9
references.pmid: 22072657
references.citation: Bioorg Med Chem Lett. 2012 Sep 1;22(17):5625-9
references.pmid: 22863203