The Roles Of Sphingomyelinase Peptides In The Disorder Of Intracellular Lipid Level Caused By ATP13A2 Deficiency

ATP13A2 gene is a member of the ATPase P5 subfamily that transports inorganic cations and other substrates.It is one of the 19 pathogenic genes of Parkinson’s disease.The importance of ATP13A2 in Parkinson’s disease emerged with the discovery of mutations in this gene causing Kufor-Rakeb syndrome.Kufor-Rakeb syndrome is an autosomal recessive Parkinson’s disease that occurs in adolescence,often accompanied by spasm,progressive supranuclear palsy and dementia.However,up to now,the molecular mechanism and regulatory pathway of ATP13A2 have not been determined.At present,a large number of brain neuroscientists have focused on the abnormal lipid metabolism in the brain tissues of patients,especially sphingomyelin and ceramide.Sphingomyelin and ceramide are essential for maintaining cell homeostasis,regulating cell pathways and completing intracellular and extracellular material exchange.Once the balance of lipid homeostasis is broken,cell damage and even death are inevitable.However,the relationship between lipid metabolism and neurodegenerative diseases is still unclear due to the wide distribution of lipids and their involvement in various cell activities.However,there is no doubt that lipid research is essential to reveal neuropathy.The purpose of this study was to determine whether ATP13A2,a Parkinson’s disease-related gene,is related to the intracellular sphingomyelin and ceramide level,and to determine the effect of ATP13A2 deletion on intracellular lipid content.In this study,fibroblasts of ATP13A2 knockout mice were obtained and the levels of sphingomyelin and ceramide in fibroblasts of ATP13A2 knockout mice were significantly increased using high performance liquid chromatography tandem mass spectrometry.On this basis,26 polypeptides designed according to sphingomyelinase were screened and endogenous sphingomyelin and ceramide levels were detected by high performance liquid chromatography tandem mass spectrometry to determine the effects of polypeptides on intracellular C16-sphingomyelin,C18-sphingomyelin,C16-ceramide and C18-ceramide metabolic levels,and whether they could alleviate or aggravate the lipid metabolic abnormalities caused by ATP13A2 deletion.The results showed that SMase-P2,SMase-P9 and SMase-P21 SMase-P22 SMase-P23 have significant effects on lipid metabolism disorders caused by ATP13A2 deletion.The results of this study not only further reveal the relationship between ATP13A2 and endogenous lipid metabolism,but also provide directions for the research and design of polypeptide drugs to alleviate abnormal lipid metabolism and useful information for the study of pathogenesis and treatment of Parkinson’s disease.