Possible association between the lrrk2 gene and anxiety behavior: a systematic literature review.

Alterations to the LRRK2 gene have been associated with Parkinson's disease and alcohol consumption in animals and humans. Furthermore, these disorders are strongly related to anxiety disorders (ADs). Thus, we investigated how the LRRK2 gene might influence anxiety in humans and mice. We elaborated a systematic review based on the PRISMA Statement of studies that investigated levels of anxiety in animal or human models with alterations in the LRRK2 gene. The search was conducted in the PubMed, Scopus, and Web of Science databases, and in reference lists with descriptors related to ADs and the LRRK2. From the 62 articles assessed for eligibility, 16 were included: 11 conducted in humans and seven, in mice. Lrrk2 KO mice and the LRRK2 G2019S, LRRK2 R1441G, and LRRK2 R1441C variants were addressed. Five articles reported an increase in anxiety levels concerning the LRRK2 variants. Decreased anxiety levels were observed in two articles, one focusing on the LRRK2 G2019S and the other, on the Lrrk2 KO mice. Eight other articles reported no differences in anxiety levels in individuals with Lrrk2 alterations compared to their healthy controls. This study discusses a possible influence between the LRRK2 gene and anxiety, adding information to the existing knowledge respecting the influence of genetics on anxiety.

Upregulation of miR-874-3p and miR-874-5p inhibits epithelial ovarian cancer malignancy via SIK2.

Based on miR-874 expression levels in the GSE47841 microarray, we hypothesized that the mature products of miR-874, miR-874-3p, or miR-874-5p, would inhibit epithelial ovarian cancer (EOC) cell proliferation, metastasis, and chemoresistance. We first examined miR-874-3p and miR-874-5p expression levels in primary EOC tumor tissue samples and found that they were significantly decreased. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) cell proliferation and transwell assays revealed that miR-874-3p and miR-874-5p significantly inhibit EOC cell proliferation, migration, and invasion. Then, using MTT and soft agar assays of paclitaxel-treated Caov3 and SKOV3 cells transfected with miR-874-3p and miR-874-5p, we found that miR-874-3p and miR-874-5p enhance EOC cell chemosensitivity. We then confirmed that serine/threonine-protein kinase 2 (SIK2) was a target gene of miR-874-3p and miR-874-5p. Overall, the results of this study indicate that SIK2 expression can serve as a prognostic biomarker for EOC and that miR-874-3p and miR-874-5p have the potential to enhance clinical treatment of EOC.

Molecular cloning and functional analysis of nucleotide-binding oligomerization domain-containing protein 1 in rainbow trout, Oncorhynchus mykiss.

NOD1 has important roles in innate immunity as sensor of microbial components derived from bacterial peptidoglycan. In this study, we identified genes encoding components of the NOD1 signaling pathway, including NOD1 (OmNOD1) and RIP2 (OmRIP2) from rainbow trout, Oncorhynchus mykiss, and investigated whether OmNOD1 has immunomodulating activity in a rainbow trout hepatoma cell line RTH-149 treated with NOD1-specific ligand (iE-DAP). The deduced amino acid sequence of OmNOD1 contained conserved CARD, NOD and LRR domains. Loss-of-function and gain-of-function experiments indicated that OmNOD1 is involved in the expression of pro-inflammatory cytokines. Silencing of OmNOD1 in RTH-149 cells treated with iE-DAP decreased the expression of IL-1ß, IL-6, IL-8 and TNF-α. Conversely, overexpression of OmNOD1 resulted in up-regulation of IL-1ß, IL-6, IL-8 and TNF-α expression. In addition, RIP2 inhibitor (gefitinib) significantly decreased the expression of these pro-inflammatory cytokines induced by iE-DAP in RTH-149 cells. These findings highlight the important role of NOD1 signaling pathway in fish in eliciting innate immune response.

Suppression of Glioblastoma Stem Cell Potency and Tumor Growth via LRRK2 Inhibition.

Leucine-rich repeat kinase 2 (LRRK2), a large GTP-regulated serine/threonine kinase, is well-known for its mutations causing late-onset Parkinson's disease. However, the role of LRRK2 in glioblastoma (GBM) carcinogenesis has not yet been fully elucidated. Here, we discovered that LRRK2 was overexpressed in 40% of GBM patients, according to tissue microarray analysis, and high LRRK2 expression correlated with poor prognosis in GBM patients. LRRK2 and stemness factors were highly expressed in various patient-derived GBM stem cells, which are responsible for GBM initiation. Canonical serum-induced differentiation decreased the expression of both LRRK2 and stemness factors. Given that LRRK2 is a key regulator of glioma stem cell (GSC) stemness, we developed DNK72, a novel LRRK2 kinase inhibitor that penetrates the blood-brain barrier. DNK72 binds to the phosphorylation sites of active LRRK2 and dramatically reduced cell proliferation and stemness factors expression in in vitro studies. Orthotopic patient-derived xenograft mouse models demonstrated that LRRK2 inhibition with DNK72 effectively reduced tumor growth and increased survival time. We propose that LRRK2 plays a significant role in regulating the stemness of GSCs and that suppression of LRRK2 kinase activity leads to reduced GBM malignancy and proliferation. In the near future, targeting LRRK2 in patients with high LRRK2-expressing GBM could offer a superior therapeutic strategy and potentially replace current clinical treatment methods.

Exercise knowledge, barriers and motivators among LRRK2 G2019S mutation carriers.

INTRODUCTION: People with a Gly2019Ser mutation in the leucine-rich repeat kinase 2 (LRRK2 G2019S) are at increased risk of developing Parkinson's disease (PD). Recent evidence suggests that exercise may delay or prevent the development of clinically overt symptoms of PD in people at risk of PD. We determined whether LRRK2 G2019S mutation carriers with and without manifest PD are aware of the relationship between exercise and PD and how they differ in awareness, barriers and motivators to exercise. METHODS: We deployed a survey among 4422 LRRK2 G2019S mutation carriers. In total, 505 (11.4%) of them completed the survey, of whom 105 had self-reported manifest PD. RESULTS: Ninety-two percent of the LRRK2 G2019S mutation carriers with manifest PD and 63% of those with non-manifest PD were aware of the relationship between exercise and PD. Lack of motivation was the top barrier for those without manifest PD, while having an injury/disability was the most common barrier for those with manifest PD. Improvement of body functioning was the top motivator for both. CONCLUSION: The fact that many at-risk individuals are not aware of the importance of exercise and would exercise more with fewer barriers creates opportunities for trials using exercise as a possible prevention strategy for PD.

LRRK2 decreases microglial actin dynamics by filamentous actin depolymerization and Rac1 inhibition.

An active actin dynamic is a crucial feature of brain microglia. Here we report that LRRK2, a primary familial Parkinson's disease-associated gene, negatively regulates microglia's actin dynamics. LRRK2 depolymerized filamentous actin (F-actin) by directly binding to it or inhibiting microglia's Rac-PAK signaling. LRRK2 knockdown resulted in a reduced ruffle and enhanced lamellipodia formation of ADP-activated microglia, altering the microglia's physiological activity to vigorous migration toward damaged cells. These results suggest that LRRK2 is a negative regulator for the controlled actin dynamics in microglia.

A Bioinformatics Approach Toward Unravelling the Synaptic Molecular Crosstalk Between Alzheimer's Disease and Diabetes.

BACKGROUND: Increasing evidence links impaired brain insulin signaling and insulin resistance to the development of Alzheimer's disease (AD). OBJECTIVE: This evidence prompted a search for molecular players common to AD and diabetes mellitus (DM). METHODS: The work incorporated studies based on a primary care-based cohort (pcb-Cohort) and a bioinformatics analysis to identify central nodes, that are key players in AD and insulin signaling (IS) pathways. The interactome for each of these key proteins was retrieved and network maps were developed for AD and IS. Synaptic enrichment was performed to reveal synaptic common hubs. RESULTS: Cohort analysis showed that individuals with DM exhibited a correlation with poor performance in the Mini-Mental State Examination (MMSE) cognitive test. Additionally, APOE ɛ2 allele carriers appear to potentially be relatively more protected against both DM and cognitive deficits. Ten clusters were identified in this network and 32 key synaptic proteins were common to AD and IS. Given the relevance of signaling pathways, another network was constructed focusing on protein kinases and protein phosphatases, and the top 6 kinase nodes (LRRK2, GSK3B, AKT1, EGFR, MAPK1, and FYN) were further analyzed. CONCLUSION: This allowed the elaboration of signaling cascades directly impacting AßPP and tau, whereby distinct signaling pathway play a major role and strengthen an AD-IS link at a molecular level.

Loss of miR-369 Promotes Tau Phosphorylation by Targeting the Fyn and Serine/Threonine-Protein Kinase 2 Signaling Pathways in Alzheimer's Disease Mice.

INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative dementia with the key pathological hallmarks amyloid-beta deposition and neurofibrillary tangles composed of hyperphosphorylated tau. microRNAs (miRNAs) are small non-coding RNAs that contribute to the pathogenesis of AD. In this study, we investigated the effect of the loss of miR-369 on the phosphorylation of tau protein and the activation of the kinases Fyn and serine/threonine-protein kinase 2 (SRPK2) as the upstream molecules facilitating tau phosphorylation in miR-369 knockout 3xTg-AD mice. METHODS: We generated miR-369 knockout 3xTg-AD mice and investigated their cognitive behaviors by maze tests. Real-time qPCR, western blot, and immunohistochemistry were performed to evaluate the expression of the miR-369 gene, phosphorylation of tau protein, and activation of Fyn and SRPK2. Luciferase reporter assays were applied to confirm the predicted targets of miR-369. RESULTS: Knocking out miR-369 in 3xTg AD mice aggravated cognitive impairment, promoted hyperphosphorylation of tau, and upregulated Fyn and SRPK2. Restoring miR-369 reversed the hyperphosphorylation of tau and downregulated Fyn and SRPK2. Additionally, miR-369 was shown to target the 3'UTRs of Fyn and SRPK2 to regulate their expression levels. CONCLUSION: Loss of miR-369 promotes tau phosphorylation by targeting the Fyn and SRPK2 signaling pathways in AD mice, and supplementation with miR-369 might be a valuable option for AD therapeutic studies.

Bivalent Ligands for Protein Degradation in Drug Discovery.

Targeting the "undruggable" proteome remains one of the big challenges in drug discovery. Recent innovations in the field of targeted protein degradation and manipulation of the ubiquitin-proteasome system open up new therapeutic approaches for disorders that cannot be targeted with conventional inhibitor paradigms. Proteolysis targeting chimeras (PROTACs) are bivalent ligands in which a compound that binds to the protein target of interest is connected to a second molecule that binds an E3 ligase via a linker. The E3 protein is usually either Cereblon or Von Hippel-Lindau. Several examples of selective PROTAC molecules with potent effect in cells and in vivo models have been reported. The degradation of specific proteins via these bivalent molecules is already allowing for the study of biochemical pathways and cell biology with more specificity than was possible with inhibitor compounds. In this review, we provide a comprehensive overview of recent developments in the field of small molecule mediated protein degradation, including transcription factors, kinases and nuclear receptors. We discuss the potential benefits of protein degradation over inhibition as well as the challenges that need to be overcome.

Nucleotide-binding oligomerization domain containing 2: structure, function, and diseases.

OBJECTIVES: To systematically review literature about the structure and function of nucleotide-binding oligomerization domain containing 2 (NOD2) and its disease association. METHODS: The English literature was searched using keywords "NOD2" and "disease". Relevant original and review articles were reviewed. RESULTS: NOD2 is an intracellular protein and shares similar molecular structure with NOD1, pyrin, and cryopyrin. There are more than 100 NOD2 gene mutations, some of which have been linked to diseases such as Crohn disease, Blau syndrome, and NOD2-associated autoinflammatory disease (NAID). The NOD2 variants located in the leucine-rich repeat (LRR) region are susceptible to Crohn disease, and the variants in the nucleotide-binding domain (NBD) and in between the NBD and LRR are associated with Blau syndrome and NAID, respectively. No disease association with the gene variants has been found in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriasis/psoriatic arthritis, adult sarcoidosis, granulomatous polyangiitis, or multiple sclerosis. The potential association of the NOD2 variants with graft-versus-host-disease remains controversial. NOD2 functions mainly through RICK or RIP2 to activate p38 mitogen-activated protein kinases and NF-κB, resulting in inflammatory response, and enhanced autophagic activity. Biologic therapy may be beneficial for NOD2-associated diseases, and new drug development may be realized based upon the signaling pathways. CONCLUSIONS: NOD2 gene mutations are associated with several diseases, and some of the mutations are of diagnostic value in Blau disease and NAID. To understand the NOD2 function, disease association, and its pathogenesis is important given the ever increasing clinical significance of NOD2.

Construction of a recombinant lentivirus containing human microRNA-7-3 and its inhibitory effects on glioma proliferation.

In the present study, we constructed a lentivirus, FIV-CMV-GFP-miR-7-3, containing the microRNA-7-3 gene and the green fluorescent protein gene, and used it to transfect human glioma U251 cells. Fluorescence microscopy showed that 80% of U251 cells expressed green fluorescence. Real-time reverse transcription PCR showed that microRNA-7-3 RNA expression in U251 cells was significantly increased. Proliferation was slowed in transfected U251 cells, and most cells were in the G1 phase of the cell cycle. In addition, the expression of the serine/threonine protein kinase 2 was decreased. Results suggested that transfection with a lentivirus carrying microRNA-7-3 can effectively suppress epidermal growth factor receptor pathway activity in U251 cells, arrest cell cycle transition from G1 phase to S phase and inhibit glioma cell growth.