The Regulatory Role Of Thioredoxin Interacting Proteins In Autophagy Of Parkinson’s Disease Through Leucine Rich Repeat Kinase 2

Parkinson’s disease is a common neurodegenerative disease,with main symptoms including limb stiffness,tremors,and decreased movement.Currently,millions of people worldwide suffer from Parkinson’s disease.Finding ways to treat and prevent Parkinson’s disease can help alleviate patients’pain and improve their quality of life.With the acceleration of the aging process of the world population,Parkinson’s disease is also increasing year by year,and the lifespan and physical health of more and more people are being challenged.Studying Parkinson’s disease can enhance our understanding of neurodegenerative diseases.The occurrence of Parkinson’s disease is related to damage to dopamine neurons in the brain.Therefore,in-depth research on Parkinson’s disease can help us better understand the operation of neurons and the function of the nervous system.This will help to better understand the pathophysiological mechanisms of other neurodegenerative diseases,thereby providing a better foundation for the treatment and prevention of these diseasesThioredoxin interacting protein(TXNIP)is aα-Members of the repressor protein family are central regulators of glucose and lipid metabolism,related to oxidative stress and inflammatory responses,and closely related to neurodegenerative diseases.Research objective:To investigate the role of TXNIP in Parkinson’s disease and explore whether it affects the LRRK2 progression of Parkinson’s disease through the molecular pathway PTEN-AKT-mTOR.Experimental method:Western Blot(WB)was used to detect the expression of TXNIP and LRRK2 in the prefrontal cortex(PFC),medial prefrontal cortex(mPFC),corpus callosum(CC),and substantia nigra of midbrain(SNpc)of MPTP induced PD mouse models.Using MPP~+to induce SH-SY5Y and PC12 cells to construct a cell PD model.Cell viability was detected using CCK-8 reagent(Cell Counting Kit-8).Western Blot(WB)was used to detect the expression of TXNIP and LRRK2 in SHSY5Y and PC12 cell line models of PD neuroblastoma cells.Results:(1)The expression of TXNIP protein in the prefrontal cortex,medial prefrontal cortex,corpus callosum,and substantia nigra compacta of PD model mice was significantly decreased,while the expression of LRRK2 protein was significantly increased.(2)The expression of AKT protein and phosphorylated AKT level in prefrontal cortex,medial prefrontal cortex,corpus callosum,and substantia nigra compacta of PD model mice were significantly reduced;The phosphorylated PTEN levels in the prefrontal cortex and substantia nigra compacta increased significantly,while the phosphorylated PTEN levels in the medial prefrontal cortex and corpus callosum showed the opposite trend and decreased significantly;The expression level of mTOR protein increased significantly in prefrontal cortex,medial prefrontal cortex and substantia nigra compacta,except that there was no significant change in the corpus callosum.(3)The expression level of p62 in the prefrontal cortex of PD model mice significantly increased,while the expression level of LC3Ⅱ significantly decreased;The expression level of p62 and LC3Ⅱ in the medial prefrontal cortex of PD model mice was significantly increased;The expression level of p62 was significantly increased in the corpus callosum of PD model mice,while the expression level of LC3Ⅱ was not significantly changed;The expression level of p62 in the dense substantia nigra of PD model mice decreased significantly,while the expression level of LC3Ⅱ increased significantly.(4)The expression level of TXNIP in the SH-SY5Y cell model induced by MPP~+was significantly increased;The expression level of LRRK2decreased significantly.Compared with the control group,the expression level and phosphorylation level of PTEN protein in the SH-SY5Y cell model induced by MPP~+were significantly reduced;The expression level of AKT protein significantly decreased;The expression level of mTOR protein significantly decreased.The expression of p62 protein significantly increased in the SH-SY5Y cell model induced by MPP~+;The expression level of LC3Ⅱ protein significantly decreased;The expression level of LC3I protein significantly increased.(5)Compared with the control group,the expression of TXNIP in the PC12 cell model induced by MPP~+significantly decreased,with a significant decrease in TXNIP in the PC12 cell model induced by0.5mM MPP~+;The expression level of LRRK2 significantly decreased under 1mM stimulation.Compared with the control group,the expression level of PTEN protein in the PC12 cell model induced by MPP~+significantly decreased while the phosphorylation level significantly increased;The expression level of AKT protein significantly decreased,and the phosphorylation level also significantly decreased;The expression of mTOR protein in PC12 cells was significantly reduced by 0.5 mM MPP~+stimulation.The expression of p62 protein in the PC12 cell model induced by MPP~+significantly decreased;The expression of LC3Ⅱ protein in PC12 cells induced by 0.25mM MPP~+significantly decreased,while the expression of LC3Ⅱ protein in PC12 cells induced by 1 mM MPP~+significantly increased.Summary:TXNIP and LRRK2 are closely related to the onset of PD,and we speculate that TXNIP may have a negative regulatory relationship with LRRK2.TXNIP may regulate LRRK2 involvement in the pathogenesis and progression of PD through the PTEN-AKT-mTOR pathway.The activation and inhibition of autophagy in PD cell models of the prefrontal cortex,medial prefrontal cortex,corpus callosum,substantia nigra compacta,SH-SY5Y and PC12 cells in PD model mice may be related to PTEN-AKT-mTOR pathway.