title: Gene and MicroRNA transcriptome analysis of Parkinson's related LRRK2 mouse models.
abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of genetic Parkinson's disease (PD). The biological function of LRRK2 and how mutations lead to disease remain poorly defined. It has been proposed that LRRK2 could function in gene transcription regulation; however, this issue remains controversial. Here, we investigated in parallel gene and microRNA (miRNA) transcriptome profiles of three different LRRK2 mouse models. Striatal tissue was isolated from adult LRRK2 knockout (KO) mice, as well as mice expressing human LRRK2 wildtype (hLRRK2-WT) or the PD-associated R1441G mutation (hLRRK2-R1441G). We identified a total of 761 genes and 24 miRNAs that were misregulated in the absence of LRRK2 when a false discovery rate of 0.2 was applied. Notably, most changes in gene expression were modest (i.e., <2 fold). By real-time quantitative RT-PCR, we confirmed the variations of selected genes (e.g., adra2, syt2, opalin) and miRNAs (e.g., miR-16, miR-25). Surprisingly, little or no changes in gene expression were observed in mice expressing hLRRK2-WT or hLRRK2-R1441G when compared to non-transgenic controls. Nevertheless, a number of miRNAs were misexpressed in these models. Bioinformatics analysis identified several miRNA-dependent and independent networks dysregulated in LRRK2-deficient mice, including PD-related pathways. These results suggest that brain LRRK2 plays an overall modest role in gene transcription regulation in mammals; however, these effects seem context and RNA type-dependent. Our data thus set the stage for future investigations regarding LRRK2 function in PD development.
authors.affiliation: Centre de recherche du CHU de Québec, CHUL, Québec, Québec, Canada ; Département de psychiatrie et de neurosciences, Université Laval, Québec, Québec, Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dorval
authors.affiliation: Center for Human Genetics, K.U.Leuven, Leuven, Belgium ; Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Mandemakers
authors.affiliation: Centre de recherche du CHU de Québec, CHUL, Québec, Québec, Canada ; Département de psychiatrie et de neurosciences, Université Laval, Québec, Québec, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Jolivette
authors.affiliation: Centre de recherche du CHU de Québec, CHUL, Québec, Québec, Canada ; Département de biologie moléculaire, biochimie médicale et pathologie, Université Laval, Québec, Québec, Canada.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Coudert
authors.affiliation: Centre de recherche du CHU de Québec, CHUL, Québec, Québec, Canada ; Département de biologie moléculaire, biochimie médicale et pathologie, Université Laval, Québec, Québec, Canada.
authors.forename: Rachid
authors.initials: R
authors.lastname: Mazroui
authors.affiliation: Center for Human Genetics, K.U.Leuven, Leuven, Belgium ; Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.affiliation: Centre de recherche du CHU de Québec, CHUL, Québec, Québec, Canada ; Département de psychiatrie et de neurosciences, Université Laval, Québec, Québec, Canada.
authors.forename: Sébastien S
authors.initials: SS
authors.lastname: Hébert
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D059467:Transcriptome
chemical_list: C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases