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Häbig, K.* ; Gellhaar, S.* ; Heim, B.* ; Djuric, V.* ; Giesert, F. ; Wurst, W. ; Walter, C.* ; Hentrich, T.* ; Riess, O.* ; Bonin, M.*

LRRK2 guides the actin cytoskeleton at growth cones together with ARHGEF7 and Tropomyosin 4.

Biochim. Biophys. Acta-Mol. Basis Dis. 1832, 2352-2367 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common genetic cause of Parkinson's disease (PD). However, LRRK2 function and molecular mechanisms causing the parkinsonian phenotype remain widely unknown. Most of LRRK2 knockdown and overexpression models strengthen the relevance of LRRK2 in regulating neurite outgrowth. We have recently identified ARHGEF7 as the first guanine nucleotide exchange factor (GEF) of LRRK2. This GEF is influencing neurite outgrowth through regulation of actin polymerization. Here, we examined the expression profile of neuroblastoma cells with reduced LRRK2 and ARHGEF7 levels to identify additional partners of LRRK2 in this process. Tropomyosins (TPMs), and in particular TPM4, were the most interesting candidates next to other actin cytoskeleton regulating transcripts in this dataset. Subsequently, enhanced neurite branching was shown using primary hippocampal neurons of LRRK2 knockdown animals. Furthermore, we observed an enhanced number of growth cones per neuron and a mislocalization and dysregulation of ARHGEF7 and TPM4 in these neuronal compartments. Our results reveal a fascinating connection between the neurite outgrowth phenotype of LRRK2 models and the regulation of actin polymerization directing further investigations of LRRK2-related pathogenesis.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Actin cytoskeleton; Parkinson's disease; Growth cone; Neurite outgrowth; Familial Parkinsons-disease; Nucleotide Exchange Factor; Induced Neurite Outgrowth; P85 Beta-pix; Kinase-activity; Isoforms; Mutation; Neurons; Pathway; Gene
ISSN (print) / ISBN 0925-4439
e-ISSN 1878-2434
Journal Biochimica et Biophysica Acta - Molecular Basis of Disease
Quellenangaben Volume: 1832, Issue: 12, Pages: 2352-2367 Article Number: , Supplement: ,
Publisher Elsevier
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)