Abstract
BackgroundDominant mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most prevalent cause of Parkinson's disease, however, little is known about the biological function of LRRK2 protein. LRRK2 is expressed in neural precursor cells suggesting a role in neurodevelopment.Methodology/Principal FindingsIn the present study, differential gene expression profiling revealed a faster silencing of pluripotency-associated genes, like Nanog, Oct4, and Lin28, during retinoic acid-induced neuronal differentiation of LRRK2-deficient mouse embryonic stem cells compared to wildtype cultures. By contrast, expression of neurotransmitter receptors and neurotransmitter release was increased in LRRK2+/− cultures indicating that LRRK2 promotes neuronal differentiation. Consistently, the number of neural progenitor cells was higher in the hippocampal dentate gyrus of adult LRRK2-deficient mice. Alterations in phosphorylation of the putative LRRK2 substrates, translation initiation factor 4E binding protein 1 and moesin, do not appear to be involved in altered differentiation, rather there is indirect evidence that a regulatory signaling network comprising retinoic acid receptors, let-7 miRNA and downstream target genes/mRNAs may be affected in LRRK2-deficient stem cells in culture.Conclusion/SignificanceParkinson's disease-linked LRRK2 mutations that associated with enhanced kinase activity may affect retinoic acid receptor signaling during neurodevelopment and/or neuronal maintenance as has been shown in other mouse models of chronic neurodegenerative diseases.
Highlights
Parkinson’s disease (PD) is the most prevalent movement disorder and is neuropathologically characterized by the selective loss of dopaminergic neurons in the substantia nigra related to motor dysfunction
The complete Genechip dataset has been loaded into ArrayExpress database under experiment E-MEXP-2963. These findings indicate that leucine-rich repeat kinase 2 (LRRK2) adopts a critical biological function during retinoic acid-induced neuronal differentiation, LRRK2 is already expressed at the embryonic stem (ES) cell stage
Hippocampal neurogenesis in adult LRRK2-deficient mice To analyse the impact of LRRK2 deficiency on neurogenesis in vivo, we investigated proliferation and differentiation of hippocampal stem cells in the subgranular zone of the dentate gyrus of adult mice
Summary
Parkinson’s disease (PD) is the most prevalent movement disorder and is neuropathologically characterized by the selective loss of dopaminergic neurons in the substantia nigra related to motor dysfunction. The etiology of PD is incompletely understood, genetic studies have identified mutations in several genes that segregate with rare familial forms of the disease [1]. Mutations in the PARK8 gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most prevalent cause of autosomal dominantly inherited PD and are characterised by typical brainstem Lewy body pathology. Several studies demonstrated that the G2019S mutation enhances kinase activity in vitro and that kinase activity mediates degeneration in transfected neurons [2,3]. Dominant mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most prevalent cause of Parkinson’s disease, little is known about the biological function of LRRK2 protein. LRRK2 is expressed in neural precursor cells suggesting a role in neurodevelopment
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