title: Changes in actin dynamics and F-actin structure both in synaptoneurosomes of LRRK2(R1441G) mutant mice and in primary human fibroblasts of LRRK2(G2019S) mutation carriers.
abstract: Converging evidence suggests that the Parkinson's disease-linked leucine-rich repeat kinase 2 (LRRK2) modulates cellular function by regulating actin dynamics. In the present study we investigate the role of LRRK2 in functional synaptic terminals of adult LRRK2-knockout and LRRK2(R1441G)-transgenic mice as well as in primary fibroblasts of LRRK2(G2019S) mutation carriers. We show that lack of LRRK2 decreases and overexpression of mutant LRRK2 age-dependently increases the effect of the actin depolymerizing agent Latrunculin A (LatA) on the synaptic cytoskeleton. Similarly, endogenous mutant LRRK2 increases sensitivity to LatA in primary fibroblasts. Under basal conditions however, these fibroblasts show an increase in F-actin bundles and a decrease in filopodial length which can be rescued by LatA treatment. Our data suggest that LRRK2 alters actin dynamics and F-actin structure both in brain neurons and skin fibroblasts. We hypothesize that increased F-actin bundling represents a compensatory mechanism to protect F-actin from the depolymerizing effect of mutant LRRK2 under basal conditions. Our data further indicate that LRRK2-dependent changes in the cytoskeleton might have functional consequences on postsynaptic NMDA receptor localization.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Diseases Research, Biberach an der Riss, Germany. Electronic address: m_caesar@gmx.de.
authors.forename: M
authors.initials: M
authors.lastname: Caesar
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Diseases Research, Biberach an der Riss, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Felk
authors.affiliation: St. Olav's University Hospital, Department of Neurology, Trondheim, Norway.
authors.forename: J O
authors.initials: JO
authors.lastname: Aasly
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Diseases Research, Biberach an der Riss, Germany. Electronic address: Frank.gillardon@boehringer-ingelheim.com.
authors.forename: F
authors.initials: F
authors.lastname: Gillardon
mesh_terms: D000199:Actins / Q000378:metabolism*; D000375:Aging / Q000378:metabolism; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010718:Phosphatidylserines / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000378:metabolism / Q000648:ultrastructure; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism* / Q000648:ultrastructure; D053778:Thiazolidines / Q000494:pharmacology
chemical_list: D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002491:Central Nervous System Agents; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D010718:Phosphatidylserines; D017346:Protein Serine-Threonine Kinases; D016194:Receptors, N-Methyl-D-Aspartate; D053778:Thiazolidines; C495280:LRRK2 protein, human; C495279:Lrrk2 protein, mouse; C037067:latrunculin A
keywords: F-actin; LRRK2; Parkinson’s disease; fibroblasts; filopodia; synaptoneurosomes