Impact Of Genetic Factors In The Pathogenesis Of Parkinson’s Disease And Paroxysmal Kinesigenic Dyskinesias

Movement Disorders refers to the motion abnormalities(excessive or lack thereof)for the outstanding performance mainly dyskinetic disorders characterized by adjusting a group of diseases.Movement disorders including the traditional concept of extrapyramidal content of the disease,the actual coverage is broader.This paper focuses on two dyskinesia diseases: Parkinson’s disease and Paroxysmal Kinesigenic Dyskinesia.There are two chapters in this research: Chapter 1.Anti-oxidative stress of UCHL1 and its involved in the pathogenesis of Parkinson’s disease.Parkinson’s disease is a common neurodegenerative disease,its main clinical manifestations are resting tremor,dystonia,bradykinesia,gait abnormalities and other motor symptoms.UCHL1 is one of the causative genes of PD and it can cause autosomal dominant hereditary PD.In addition,it has been found that UCHL1 protein levels decrease in sporadic PD.Currently UCHL1 pathogenic mechanism is not clear until now.To investigate the function of UCHL1,we used a small interfering RNA(Si RNA)technology to the reduce the protein expression of UCHL1 and it was found to be more sensitive to nerve poisons(MPP+)stimulation,manifested as decreased cell viability,increased apoptosis proteins level and declined mitochondrial membrane potential.While overexpressed UCHL1 could save the process.Through co-immunoprecipitation we found Mortalin interactions with UCHL1,and UCHL1 could ubiqutinate Mortalin as a ubiquitin ligase and then mediated Mortalin to mitochondrial localization.Chapter 2.The pathogenesis of PRRT2 truncated mutations lead to Paroxysmal Kinesigenic Dyskinesia.Paroxysmal Kinesigenic Dyskinesia is an episodic involuntary movement disorder characterized by recurrent and brief involuntary movement.Proline-rich transmembrane protein 2(PRRT2)has been identified as the causative gene of PKD.So far it have been found a variety of mutant forms of PRRT2: point mutations,frameshift mutations,deletion mutations,insertion mutations,of which the most common mutation is truncated mutantion.We chose three kinds of truncated mutants,including the hotspots c649 dup C as the research object.In the present study,low expression of truncated PRRT2 was detected and was further rescued by applying the inhibitor of Nonsense-mediated m RNA decay(NMD)pathway and silencing regulator of nonsense transcripts 1(UPF1),suggesting that NMD plays an important role in the pathogenesis of PKD by haploinsufficiency.Moreover,a small portion of undegraded mutant m RNA was translated to truncated protein which changed its cellular localization from membrane to cytoplasm that may result in functional loss.The NMD of truncated mutation of PRRT2 and alteration function of undegraded of PRRT2,we speculate,might lead to PKD.