Adenosine A1 receptor ligands bind toα-synuclein:implications forα-synuclein misfolding andα-synucleinopathy in Parkinson’s disease  

作　　者：Elisabet Jakova Mohamed Taha Moutaoufik Jeremy S.Lee Mohan Babu Francisco S.Cayabyab 

机构地区：[1]Department of Surgery,College of Medicine,University of Saskatchewan,Saskatoon,SK,Canada [2]Department of Chemistry and Biochemistry,Faculty of Science,University of Regina,Regina,SK,Canada [3]Department of Biochemistry,Microbiology and Immunology,College of Medicine,University of Saskatchewan,Saskatoon,SK,Canada.

出　　处：《Translational Neurodegeneration》2022年第1期809-834,共26页转化神经变性病（英文）

基　　金：the Animal Review and Ethics Board(AREB)of the University of Saskatchewan(Animal Use Protocol#20070090).

摘　　要：Background:Accumulatingα-synuclein(α-syn)aggregates in neurons and glial cells are the staples of many synucleinopathy disorders,such as Parkinson’s disease(PD).Since brain adenosine becomes greatly elevated in ageing brains and chronic adenosine A1 receptor(A1R)stimulation leads to neurodegeneration,we determined whether adenosine or A1R receptor ligands mimic the action of known compounds that promoteα-syn aggregation(e.g.,the amphetamine analogue 2-aminoindan)or inhibitα-syn aggregation(e.g.,Rasagiline metabolite 1-aminoindan).In the present study,we determined whether adenosine,A1R receptor agonist N^(6)-Cyclopentyladenosine(CPA)and antago-nist 8-cyclopentyl-1,3-dipropylxanthine(DPCPX)could directly interact withα-syn to modulateα-syn aggregation and neurodegeneration of dopaminergic neurons in the substantia nigra(SN).Methods:Nanopore analysis and molecular docking were used to test the binding properties of CPA and DPCPX withα-syn in vitro.Sprague-Dawley rats were administered with 7-day intraperitoneal injections of the A1R ligands and 1-and 2-aminoindan,and levels ofα-syn aggregation and neurodegeneration were examined in the SN pars compacta and hippocampal regions using confocal imaging and Western blotting.Results:Using nanopore analysis,we showed that the A1R agonists(CPA and adenosine)interacted with the N-terminus ofα-syn,similar to 2-aminoindan,which is expected to promote a“knot”conformation andα-syn misfolding.In contrast,the A1R antagonist DPCPX interacted with the N-and C-termini ofα-syn,similar to 1-aminoindan,which is expected to promote a“loop”conformation that preventsα-syn misfolding.Molecular docking studies revealed that adenosine,CPA and 2-aminoindan interacted with the hydrophobic core ofα-syn N-terminus,whereas DPCPX and 1-aminoindan showed direct binding to the N-and C-terminal hydrophobic pockets.Confocal imaging and Western blot analyses revealed that chronic treatments with CPA alone or in combination with 2-aminoindan increasedα-syn expression/aggregation

关 键 词：Alpha-synucleinopathy Adenosine A1 receptor N6-cyclopentyladenosine 8-cyclopentyl-1 3-dipropylxanthine 1-aminoindan 2-aminoindan Neuroprotection Neurodegeneration Protein misfolding 

分 类 号：R742.5[医药卫生—神经病学与精神病学]