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

Translational Neurodegeneration 2023年第1期12卷 479-499页

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 Department of Molecular Neurology University Hospital ErlangenFriedrich-Alexander University Erlangen-Nürnberg91054 ErlangenGermany Institute of Biochemistry Christian-Albrechts-University KielKielGermany The Ken and Ruth Davee Department of Neurology Northwestern University Feinberg School of MedicineChicagoIL 60611USA.

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 pathology the synaptic protein alpha-synuclein(αSyn)converts from a soluble monomer to oligomeric structures and insoluble amyloid *** aim of this study was to unravel the effect ofαSyn aggregates on lysosomal turnover,particularly focusing on lysosomal homeostasis and *** these enzymes have been shown to be directly involved in the lysosomal degradation ofαSyn,impairment of their enzymatic capacity has extensive *** 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 *** 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 *** 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 *** Our findings demonstrate a strong interplay betweenαSyn aggregation pathways and function of lysosomal *** 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

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