title: The parkinson's disease-associated LRRK2 mutation R1441G inhibits neuronal differentiation of neural stem cells.
abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause familial as well as sporadic Parkinson's disease (PD) that is characterized by an age-dependent degeneration of dopaminergic neurons. LRRK2 is strongly expressed in neural stem cells (NSCs), but still the exact molecular function of LRRK2 in these cells remains unknown. By performing a systemic analysis of the gene expression profile of LRRK2-deficient NSCs, we found that the expression of several PD-associated genes, such as oxidation and reduction in mitochondria, are deregulated on LRRK2 absence. Our data, indeed, indicate that LRRK2 regulates the level of cellular oxidative stress and thereby influences the survival of NSCs. Furthermore, the lack of LRRK2 leads to an up-regulation of neuronal differentiation-inducing processes, including the Let-7a pathway. On the other hand, the constitutive mutant of LRRK2(R1441G), known to cause PD, leads to down-regulation of the same pathway. In agreement with the function of Let-7a during neuronal differentiation, LRRK2-deficient NSCs differentiate faster than wild-type cells, while LRRK2(R1441G)-expressing NSCs show impaired neuronal differentiation. These results might help better characterize the molecular mechanisms underlying the role of LRRK2 in NSCs and would further improve potential cell-replacement strategies as well as drug discovery approaches.
authors.affiliation: Stem Cell Biology and Regeneration Group, ZMBE, Institute of Cell Biology, Westfälische Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Lamia'a
authors.initials: L
authors.lastname: Bahnassawy
authors.forename: Sarah
authors.initials: S
authors.lastname: Nicklas
authors.forename: Thomas
authors.initials: T
authors.lastname: Palm
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Menzl
authors.forename: Fabian
authors.initials: F
authors.lastname: Birzele
authors.forename: Frank
authors.initials: F
authors.lastname: Gillardon
authors.forename: Jens C
authors.initials: JC
authors.lastname: Schwamborn
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs; C542687:mirnlet7 microRNA, mouse; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases