A Molecular Mechanism Study On The Influence Of Genetic Factors Of The GRN Gene Mutation And Metabolic Factors Of Type 2 Diabetes Mellitus On Parkinson's Syndrome

Parkinson's syndrome is a series of clinical syndromes with similar symptoms.In a broad sense,Parkinson's disease syndrome includes degenerative diseases such as primary Parkinson's disease,secondary Parkinson's syndrome,Parkinson's superposition syndrome(PPS)and hereditary Parkinson's syndrome.Clinically,middle-aged and elderly people are prone to motor these symptoms,such as static tremor,myotonia,bradykinesia and postural reflex disorder.Many factors can induce Parkinson's syndrome,and the manifestations of Parkinson's syndrome induced by different types of factors are also different.Some treatment methods are quite opposite,so it needs to be distinguished according to different etiologies.This paper will study two types of Parkinson's syndrome caused by two factors.Genetic factors:GRN gene mutation makes patients have a special clinical phenotype of FTD combined with PSPBackground:GRN(granule precursor protein)gene mutation is the main cause of FTD(frontotemporal dementia).We found a special FTD patient with typical FTD dementia symptoms accompanied by PSP(supranuclear palsy)related symptoms.Methods:brain MRI and PET/CT imaging were used to further confirm the diagnosis of FTD.Gene sequencing and apoptosis and survival test were carried out to determine the function of mutant GRN.Results:a new missense GRN mutation was found in this patient(c.1498g>A,p.v500i).Wild type GRN gene plays a nutritional maintenance function to maintain the survival of SH-SY5Y cells in serum-free medium,while GRN mutation(c.1498g>A,p.v500i)may not be able to polymerize into PGRN protein through structural changes,damaging the ability to maintain cell survival.Conclusion:FTD with bvftd and PSP characteristics in the same patient can be considered as a specific phenotype of patients with GRN mutation.The mutation of GRN p.v500i may lead to the degeneration of neurons in vitro and the production of PSP,which may be a new pathogenic mutation in patients with FTD.Metabolic factors:molecular mechanism of the effect of type 2 diabetes on primary Parkinson's disease.Background:Patients with type 2 diabetes mellitus(T2DM)have a higher probability of suffering from Parkinson's disease(PD)than normal people,and the symptoms of Parkinson's syndrome appear earlier and more severe.Methods:the experimental animal model of T2DM combined with PD was established.The molecular mechanism of type 2 diabetes promoting the occurrence and development of Parkinson's disease was explored by metabonomics,Western blot and immunofluorescence staining.Results:the integrity of blood-brain barrier was damaged more seriously and the number of pericytes decreased significantly in T2DM combined with PD mouse model;At the same time,the levels of metabolic components glucose and membrane GLUT4(glucose transporter 4)decreased significantly ?-The increase of syn protein expression,mitochondrial autophagy dysfunction and reactive oxygen species level can restore the symptoms of PD by giving GLUT4 agonist in vivo or removing influencing factors in vitro.Conclusion:in experimental animals,T2DM may destroy peripheral cells in microvascular units and increase the destruction of blood-brain barrier,so that it can act on neurons through the blood-brain barrier;On the other hand,insulin resistance reduces the level of functional GLUT4 in cell membrane,which leads to abnormal energy metabolism of neurons ? Abnormal synuclein aggregation and mitochondrial autophagy dysfunction are accompanied by the increase of oxidative stress level.Increasing the level of GLUT4 can improve the PD symptoms of experimental animals.