Project description:Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial and sporadic ParkinsonM-bM-^@M-^Ys disease (PD). Here, we investigated in parallel gene and microRNA transcriptome profiles of three different LRRK2 mouse models. Striatal tissue was isolated from adult LRRK2 knockout mice, as well as mice expressinghuman LRRK2 wildtype (hLRRK2-WT) or PD-associated R1441G mutation (hLRRK2-R1441G). We used microarraya to measure gene and microRNA expression levels in various LRRK2 mouse models. LRRK2 wildtype and knockout mice were bred on a C57BL/6 background. LRRK2 non-transgenic and hLRRK2 transgenic mice were bred on a FVB/N background.
Project description:Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial and sporadic Parkinson’s disease (PD). Here, we investigated in parallel gene and microRNA transcriptome profiles of three different LRRK2 mouse models. Striatal tissue was isolated from adult LRRK2 knockout mice, as well as mice expressinghuman LRRK2 wildtype (hLRRK2-WT) or PD-associated R1441G mutation (hLRRK2-R1441G).
Project description:Numerous leucine-rich repeat kinase 2 mutations identified throughout the protein are associated with Parkinson disease, however the activating G2019S kinase domain mutation is currently regarded as the most common cause of familial and sporadic forms of this disorder. Despite studies demonstrating the prominent role that its kinase activity plays in the pathobiology of leucine-rich repeat kinase 2, few substrates have been identified and only a subset of these have been linked to disease. Therefore, we utilized protein microarrays to screen over 9,000 human proteins in an unbiased radiometric assay for potential targets of the kinase.
Project description:The Ndr (nuclear Dbf2-related) family members are highly conserved serine/threonine protein kinases, which function in many cellular processes extending from cytokinesis to neurite outgrowth. In humans, the NDR2 gene is located in a microduplication hotspot on chromosome 12p that is associated with intellectual disabilities in several individuals. To address a putative contribution of Ndr2 overexpression to such cognitive dysfunctions we generated conditional transgenic mice overexpressing Ndr2 in postmigratory forebrain neurons. Proteomic analysis identifies several interaction partners of transgenic Ndr2 relevant to MF maturation. including the leucin-rich repeat kinase 2 (Lrrk2).
Project description:Bulk RNA expression profiles were captured from hearts of Leucine-rich repeat containing protein 10 (Lrrc10) knockout (KO) and wild type (WT) mice that underwent myocardial infarction (MI) or sham (SH) surgery at postnatal day 1 and full ventricle collection at 7 days post-surgery
Project description:Mutations in leucine-rich repeat kinase 2 (LRRK2) segregate with familial Parkinson’s disease (PD) and genetic variation in LRRK2 contributes to risk of sporadic disease. Although knockout of LRRK2 or knock-in of pathogenic mutations into the mouse germline does not result in a PD phenotype, several defects have been reported in the kidneys of LRRK2 knockout mice. To understand LRRK2 function in vivo, we used an unbiased approach to determine which protein pathways are affected in LRRK2 knockout kidneys. We performed two iTRAQ screens on cytosol- and microsome-enriched fractions from 12-month old LRRK2-KO and G2019S knockin kidneys compared to wild type controls. We nominated changes in cytoskeletal-associated proteins, lysosomal proteases, proteins involved in vesicular trafficking and in control of protein translation in LRRK2-KO. Changes were not seen in mice expressing the pathogenic G2019S LRRK2 mutant.
Project description:Genetic mutations on leucine-rich repeat kinase 2 (LRRK2) have been associated with an increased risk of Parkinson's disease. The Gly2019Ser (G2019S) mutation on LRRK2 gene is a relatively common cause of familial Parkinson's disease in Caucasian population. In this study, we generated H9 hESC harboring LRRK2 (G2019S) mutation by gene knockin. Wildtype and LRRK2 mutant hESC were differentiated into NSC using a chemically defined protocol.
