The G2019S LRRK2 mutation increases myeloid cell chemotactic responses and enhances LRRK2 binding to actin-regulatory proteins.
The Leucine rich repeat kinase 2 (LRRK2) gene is genetically and biochemically linked to several diseases that involve innate immunity. LRRK2 protein is highly expressed in phagocytic cells of the innate immune system, most notably in myeloid cells capable of mounting potent pro-inflammatory responses. Knockdown of LRRK2 protein in these cells reduces pro-inflammatory responses. However, the effect of LRRK2 pathogenic mutations that cause Parkinson's disease on myeloid cell function is not clear but could provide insight into LRRK2-linked disease. Here, we find that rats expressing G2019S LRRK2 have exaggerated pro-inflammatory responses and subsequent neurodegeneration after lipopolysaccharide injections in the substantia nigra, with a marked increase in the recruitment of CD68 myeloid cells to the site of injection. While G2019S LRRK2 expression did not affect immunological homeostasis, myeloid cells expressing G2019S LRRK2 show enhanced chemotaxis both in vitro in two-chamber assays and in vivo in response to thioglycollate injections in the peritoneum. The G2019S mutation enhanced the association between LRRK2 and actin-regulatory proteins that control chemotaxis. The interaction between G2019S LRRK2 and actin-regulatory proteins can be blocked by LRRK2 kinase inhibitors, although we did not find evidence that LRRK2 phosphorylated these interacting proteins. These results suggest that the primary mechanism of G2019S LRRK2 with respect to myeloid cell function in disease may be related to exaggerated chemotactic responses.
Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics.
Mark S
MS
Moehle
Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics.
João Paulo Lima
JP
Daher
Department of Surgery.
Travis D
TD
Hull
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA and.
Ravindra
R
Boddu
Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics.
Hisham A
HA
Abdelmotilib
Department of Surgery.
James
J
Mobley
Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
George T
GT
Kannarkat
Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Malú G
MG
Tansey
Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, abwest@uab.edu.
Andrew B
AB
West
D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002633:Chemotaxis / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology
D000199:Actins; C547428:LRRK2 protein, rat; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases