LRRK2 guides the actin cytoskeleton at growth cones together with ARHGEF7 and Tropomyosin 4.
Biochim Biophys Acta
; 1832(12): 2352-67, 2013 Dec.
Article
em En
| MEDLINE
| ID: mdl-24075941
ABSTRACT
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.
Palavras-chave
Actin cytoskeleton; F-actin; G-actin; GEF; Growth cone; LIM domain kinase; LIMK; LRRK2; Neurite outgrowth; PAK; Parkinson's disease; TPM; filamentous actin; globular actin; guanine nucleotide exchange factor; leucine-rich repeat kinase 2; p21 protein (Cdc42/Rac)-activated kinase; qRT-PCR; quantitative reverse transcription polymerase chain reaction; shRNA; short hairpin RNA; siRNA; small interfering RNA; tropomyosin
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tropomiosina
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Citoesqueleto de Actina
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Proteínas Serina-Treonina Quinases
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Cones de Crescimento
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Fatores de Troca de Nucleotídeo Guanina Rho
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Biochim Biophys Acta
Ano de publicação:
2013
Tipo de documento:
Article