Progress of the possible mechanism of leucine-rich repeat kinase 2 affecting thyroid cancer via regulating autophagy / 肿瘤研究与临床

Thyroid cancer is the most common malignant tumor of the endocrine system, and the incidence is increasing year by year, which seriously threatens people's health. Autophagy is a programmed mode of death that can be used as a potential target for anti-tumor therapy and plays an important regulatory role. Leucine-rich repeat kinase 2 (LRRK2) is a protein kinase encoded by PARK8 gene. The recent studies have confirmed that autophagy is closely related to thyroid cancer. This paper analyzes the possible regulatory mechanism of LRRK2 affecting thyroid cancer through autophagy, providing new ideas for basic research and clinical diagnosis and treatment of thyroid cancer.

The therapeutic effect of quercetin on the transgenic PD drosophila model with LRRK2 mutation / 西安交通大学学报(医学版)

Objective: To study the therapeutic effect and mechanism of quercetin on Parkinson's disease (PD) model induced by a leucine-rich repeat kinase 2 (LRRK2) gene mutation. Methods: PD transgenic drosophila model Ddc-Gal4; UAS-LRRK2/G2019S was generated by Gal4/UAS hybridization and selectively expressed G2019S mutant LRRK2 in dopaminergic neurons. PD transgenic drosophila and control were fed with corn medium supplemented with quercetin in 1, 10 and 100 μmol/L for the treatment group, or with standard corn medium in PD model group and blank control group. The life span and locomotor ability were observed and compared between the quercetin treatment group and the PD drosophila model group. The brains of the drosophila were dissected and stained with TH immunofluorescence antibody to observe the survival rate of dopaminergic neurons. The brain tissues were also measured with Western blot to detect the protein expression levels of TH, GCLC, p-LRRK2, and p-p38MAPK. Results: The group treated with 10 μmol/L quercetin showed the best therapeutic effect on the prolongation of life span and improvement of locomotor ability compared with PD transgenic drosophila model without any treatment. The locomotor activity of drosophila was significantly improved at week 6 and the loss of dopaminergic neurons in the brain of the PD model drosophila was effectively diminished by quercetin. Quercetin also significantly lowered the level of phosphorylated LRRK2 in the PD transgenic drosophila compared with the PD model group (P<0.05), indicating the inhibiting effect of quercetin on the activity of LRRK2 kinase of the PD model. In addition, quercetin could activate the antioxidant-signaling pathway and inhibit the p38MAPK signaling pathway. Results: Quercetin can activate the antioxidant-signaling pathway and inhibit the LRRK2 kinase activity, which can further regulate MAPK signaling pathway and reduce the neurotoxicity of LRRK2 mutation and protect dopaminergic neurons in PD transgenic drosophila model.

LRRK2/NF-κB signaling modulates inflammatory responses in BCG-in-fected RAW264.7 macrophages / 中国病理生理杂志

AIM:To investigate the biological function and potential mechanism of leucine-rich repeat kinase 2 (LRRK2)in RAW264.7 macrophages during Mycobacterium tuberculosis infection.METHODS: The bacillus Calmette-Guerin(BCG)-infected RAW264.7 cell model was established.Colony-forming unit(CFU)analysis was used to deter-mine the mycobacterial viability.The releases of interleukin(IL)-1β,IL-6 and interferon-γ(IFN-γ)in the RAW264.7 cells were detected by ELISA.qPCR and Western blot were used to measure the mRNA and protein expression levels,re-spectively.RESULTS:LRRK2 was robustly enhanced in the RAW264.7 cells in response to BCG infection.Additional-ly,silencing of LRRK2 suppressed intracellular growth of mycobacteria during BCG challenge.Moreover, silencing of LRRK2 dramatically attenuated the accumulation of inflammatory cytokines IL-1β,IL-6 and IFN-γinduced by BCG infec-tion.More importantly,LRRK2 modulated BCG-induced inflammatory responses by positively regulating the nuclear factor-κB(NF-κB)signaling pathway.CONCLUSION: LRRK2/NF-κB signaling pathway positively modulates inflammatory responses during BCG infection,which may provide a better understanding of the pathogenesis of tuberculosis and useful in -formation for developing potential therapeutic interventions against the disease.

Leucine-rich repeat kinase 2 inhibitor as Parkinson′s disease novel therapeutics:research advances / 国际药学研究杂志

Parkinson′s disease(PD)is a common disease caused by multiple factors and characterized by pathological degen?eration in the dopaminergic neural system. Based on its pathogenic factors,PD can be divided into several subtypes,so it is essential to develop therapeutic agents based on the main pathogenic factor of each subtype of PD. Recently it is confirmed that the mutation of leucine-rich repeat kinase 2(LRRK2)gene leads to increased activity of the LRRK2 notably,and then causes neurodegeneration. Thus developing LRRK2 inhibitors to modulate the kinase activity will be a novel therapy for the PD subtype which is caused by LRRK2 gene mutation. LRRK2,either a kinase or a GTPase,has two drug binding sites. Therefore,two types of LRRK2 inhibitors are being studied,one is the kinase inhibitor and the other is GTPase inhibitor. This paper summarizes the recent progress in the dis?covery and development of LRRK2 inhibitors.

Leucine-rich repeat kinase 2 inhibitor as Parkinson’s disease novel therapeutics: Research advances / 国际药学研究杂志

Parkinson’s disease PD is a common disease caused by multiple factors and characterized by pathological degeneration in the dopaminergic neural system. Based on its pathogenic factors, PD can be divided into several subtypes, so it is essential to develop therapeutic agents based on the main pathogenic factor of each subtype of PD. Recently it is confirmed that the mutation of leucine- rich repeat kinase 2 LRRK2 gene leads to increased activity of the LRRK2 notably, and then causes neurodegeneration. Thus developing LRRK2 inhibitors to modulate the kinase activity will be a novel therapy for the PD subtype which is caused by LRRK2 gene mutation. LRRK2, either a kinase or a GTPase, has two drug binding sites. Therefore, two types of LRRK2 inhibitors are being studied, one is the kinase inhibitor and the other is GTPase inhibitor. This paper summarizes the recent progress in the discovery and development of LRRK2 inhibitors.