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RECIPROCAL EFFECTS OF ALPHA-SYNUCLEIN AGGREGATION AND LYSOSOMAL HOMEOSTASIS IN IPSC-DERIVED SYNUCLEINOPATHY MODELS
Abstract
Aims
Lysosomal dysfunction has been implicated in a number of neurodegenerative diseases such as Parkinson’s disease (PD). Various molecular, clinical and genetic studies emphasize a central role of lysosomal pathways and proteins contributing to the pathogenesis of PD. Within PD pathology the synaptic protein alpha-synuclein (aSyn) converts from a soluble monomer into insoluble amyloid fibrils. The aim of our study is to unravel the effect of aSyn aggregates on lysosomal turnover, in particular focusing on lysosomal homeostasis and cathepsins. Since these enzymes have been shown to be directly involved in the lysosomal degradation of aSyn, impairment of their enzymatic capacity has extensive consequences.
Methods
In our study we are applied state-of-the-art technology of patient-derived induced pluripotent stem cells (iPSCs) to examine the effect of intracellular, pathological aSyn conformers, on cell homeostasis and lysosomal function on dopaminergic neurons by biochemical analyses.
Results
We showed in patient-derived dopaminergic neurons with synuclein aggregation an impaired lysosomal trafficking of cathepsins resulting in reduced proteolytic activity of cathepsins in the lysosome. Additionally, by using a small compound boosting trafficking towards the lysosome, we were able to rescue cathepsin function.
Conclusions
Our findings demonstrate a strong interplay between aSyn aggregation pathways and function of lysosomal cathepsins. It appears that aSyn directly interferes with enzymatic activity of cathepsins which might lead to a vicious cycle of impaired alpha-synuclein degradation.