Identifying genetic targets in clinical subtypes of Parkinson’s disease for optimizing pharmacological treatment strategies  

作　　者：Dewen Kong Cao Li LingYan Ma Lida Du Nan Jiang Xiaoyue Zhao Sen Zhang Zhigang Zhao Lianhua Fang Guanhua Du 

机构地区：[1]State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Beijing Key Laboratory of Drug Target Identification and Drug Screening,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China [2]Department of Pharmacy,Beijing Tiantan Hospital,Capital Medical University,Beijing,China [3]Center for Movement Disorders,Department of Neurology,Beijing Tiantan Hospital,Capital Medical University,Beijing,China [4]China National Clinical Research Center for Neurological Diseases,Beijing,China [5]Institute of Molecular Medicine&Innovative Pharmaceutics,Qingdao University,Qingdao,China [6]School of Pharmacy,Henan University,Kaifeng,China [7]Medical Science Research Center,Peking Union Medical College Hospital,Chinese Academy of Medical Science and Peking Union Medical College,Beijing,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第12期5708-5719,共12页信号转导与靶向治疗(英文)

基　　金：supported by Beijing Natural Science Foundation(7232258);the CAMS Innovation Fund for Medical Sciences(2022-I2M-1-005);the Key R&D Program of Shan Dong Province(No.2019JZZY020909).

摘　　要：The heterogeneity of Parkinson’s disease(PD)has been recognized in clinical,with patients categorized into distinct subsets based on motor phenotype,such as tremor-dominant PD(TD),postural instability and gait difficulty-dominant PD(PIGD)and mixed PD(Mix).Despite this categorization,the underlying mechanisms of this heterogeneity remain poorly understood,and there is no personalized effective treatment for each PD subtype.To address this,a rat model for PD subtypes was established by unilateral stereotaxic injection of 6-OHDA,followed by cluster analysis of behavioral data.The serum neurofilament light chain(NfL)and uric acid(UA)levels as well as alterations in brain autonomic activity in rats were consistent with clinical patients,and metabolomics results showed that more than 70%of the metabolites in the serum of different subtypes of PD rats and clinical patients appeared to be consistently altered.Further transcriptomic analysis by RNA-seq has elucidated that the development of PD subtypes is associated with altered gene expression in neurotransmitter,neuronal damage in the central or peripheral nervous system,and lipid metabolism.In addition,based on the subtype-specific differentially expressed genes,25 potential drug candidates were identified.Notably,the Alox15 inhibitor baicalein showed a greater efficacy on Mix rats,highlighting the possibility of selecting targeted treatments for well-defined individuals.

关 键 词：clinical SUBTYPES alterations 

分 类 号：R742.5[医药卫生—神经病学与精神病学]