Gene and MicroRNA transcriptome analysis of Parkinson's related LRRK2 mouse models
Véronique Dorval1, Wim Mandemakers2, Francis Jolivette1
1Centre de recherche du CHU de Québec, CHUL, Québec, Québec, Canada ; Département de psychiatrie et de neurosciences, Université Laval, Québec, Québec, Canada.
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.
Insights
Genetic Parkinson's disease (PD) is linked to leucine-rich repeat kinase 2 (LRRK2) mutations. This study reveals LRRK2 influences gene and microRNA (miRNA) expression in mouse models, suggesting a modest role in brain transcription regulation.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD).
- The precise biological function of LRRK2 and its role in PD pathogenesis are not fully understood.
- Previous research proposed LRRK2 involvement in gene transcription regulation, but this remains debated.
Purpose of the Study:
- To investigate the role of LRRK2 in gene and microRNA (miRNA) transcriptome regulation.
- To analyze transcriptome profiles in different LRRK2 mouse models, including knockout and human mutation expression.
- To identify LRRK2-dependent regulatory networks and their relevance to Parkinson's disease.
Main Methods:
- Comparative analysis of gene and miRNA expression profiles in striatal tissue from LRRK2 knockout, wildtype, and mutant human LRRK2 mouse models.
- Utilized RNA sequencing and real-time quantitative RT-PCR for transcriptome profiling and validation.
- Bioinformatics analysis to identify dysregulated gene and miRNA networks.
Main Results:
- In LRRK2 knockout mice, 761 genes and 24 miRNAs were misregulated, with most gene expression changes being modest (<2 fold).
- Expression of human LRRK2 wildtype or R1441G mutant showed minimal impact on overall gene expression but altered some miRNA levels.
- Bioinformatics analysis revealed dysregulated miRNA-dependent and independent networks, including PD-related pathways, in LRRK2-deficient mice.
Conclusions:
- Brain LRRK2 appears to have a modest role in mammalian gene transcription regulation.
- The effects of LRRK2 on transcription are context- and RNA type-dependent.
- These findings provide a foundation for further research into LRRK2's function in Parkinson's disease development.
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