Reciprocal effects of alpha-synuclein aggregation and lysosomal homeostasis in synucleinopathy models  

作　　者：Alice Drobny Fanni Annamária Boros Denise Balta Susy Prieto Huarcaya Deniz Caylioglu Niyeti Qazi Julia Vandrey Yanni Schneider Jan Philipp Dobert Caleb Pitcairn Joseph Robert Mazzulli Friederike Zunke 

机构地区：[1]Department of Molecular Neurology,University Hospital Erlangen,Friedrich-Alexander University Erlangen-Nürnberg,91054 Erlangen,Germany [2]Institute of Biochemistry,Christian-Albrechts-University Kiel,Kiel,Germany [3]The Ken and Ruth Davee Department of Neurology,Northwestern University Feinberg School of Medicine,Chicago,IL 60611,USA.

出　　处：《Translational Neurodegeneration》2023年第1期479-499,共21页转化神经变性病（英文）

基　　金：supported by the Deutsche Forschungsgemeinschaft(DFG),Bonn,Germany(SFB877,project B11,Grant no.:125440785);the Interdisciplinary Center for Clinical Research(IZKF)at the University Hospital of the University of Erlangen-Nuremberg(Jochen-Kalden funding programme N8);Research reported in this publication was partly supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number R01NS092823 and RF1NS109157.

摘　　要：Background Lysosomal dysfunction has been implicated in a number of neurodegenerative diseases such as Parkinson’s disease(PD).Various molecular,clinical and genetic studies have highlighted a central role of lysosomal pathways and proteins in the pathogenesis of PD.Within PD pathology the synaptic protein alpha-synuclein(αSyn)converts from a soluble monomer to oligomeric structures and insoluble amyloid fibrils.The aim of this study was to unravel the effect ofαSyn aggregates on lysosomal turnover,particularly focusing on lysosomal homeostasis and cathepsins.Since these enzymes have been shown to be directly involved in the lysosomal degradation ofαSyn,impairment of their enzymatic capacity has extensive consequences.Methods We used patient-derived induced pluripotent stem cells and a transgenic mouse model of PD to examine the effect of intracellularαSyn conformers on cell homeostasis and lysosomal function in dopaminergic(DA)neurons by biochemical analyses.Results We found impaired lysosomal trafficking of cathepsins in patient-derived DA neurons and mouse models withαSyn aggregation,resulting in reduced proteolytic activity of cathepsins in the lysosome.Using a farnesyltransferase inhibitor,which boosts hydrolase transport via activation of the SNARE protein ykt6,we enhanced the maturation and proteolytic activity of cathepsins and thereby decreasedαSyn protein levels.Conclusions Our findings demonstrate a strong interplay betweenαSyn aggregation pathways and function of lysosomal cathepsins.It appears thatαSyn directly interferes with the enzymatic function of cathepsins,which might lead to a vicious cycle of impairedαSyn degradation.

关 键 词：Dopaminergic neurons iPSC-derived models LYSOSOME Parkinson’s disease Protein trafficking SYNUCLEINOPATHY 

分 类 号：R741[医药卫生—神经病学与精神病学]