TY - JOUR
T1 - Reciprocal effects of alpha-synuclein aggregation and lysosomal homeostasis in synucleinopathy models
AU - Drobny, Alice
AU - Boros, Fanni Annamária
AU - Balta, Denise
AU - Prieto Huarcaya, Susy
AU - Caylioglu, Deniz
AU - Qazi, Niyeti
AU - Vandrey, Julia
AU - Schneider, Yanni
AU - Dobert, Jan Philipp
AU - Pitcairn, Caleb
AU - Mazzulli, Joseph Robert
AU - Zunke, Friederike
N1 - Funding Information:
Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany (SFB877, project B11, Grant no.: 125440785) and 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. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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 of αSyn 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 of αSyn, 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 intracellular αSyn 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 with αSyn 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 decreased αSyn protein levels. Conclusions: Our findings demonstrate a strong interplay between αSyn aggregation pathways and function of lysosomal cathepsins. It appears that αSyn directly interferes with the enzymatic function of cathepsins, which might lead to a vicious cycle of impaired αSyn degradation. Graphical abstract: Lysosomal trafficking of cathepsin D (CTSD), CTSL and CTSB is disrupted when alpha-synuclein (αSyn) is aggregated. This results in a decreased proteolytic activity of cathepsins, which directly mediate αSyn clearance. Boosting the transport of the cathepsins to the lysosome increases their activity and thus contributes to efficient αSyn degradation.[Figure not available: see fulltext.]
AB - 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 of αSyn 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 of αSyn, 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 intracellular αSyn 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 with αSyn 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 decreased αSyn protein levels. Conclusions: Our findings demonstrate a strong interplay between αSyn aggregation pathways and function of lysosomal cathepsins. It appears that αSyn directly interferes with the enzymatic function of cathepsins, which might lead to a vicious cycle of impaired αSyn degradation. Graphical abstract: Lysosomal trafficking of cathepsin D (CTSD), CTSL and CTSB is disrupted when alpha-synuclein (αSyn) is aggregated. This results in a decreased proteolytic activity of cathepsins, which directly mediate αSyn clearance. Boosting the transport of the cathepsins to the lysosome increases their activity and thus contributes to efficient αSyn degradation.[Figure not available: see fulltext.]
KW - Dopaminergic neurons
KW - Lysosome
KW - Parkinson’s disease
KW - Protein trafficking
KW - Synucleinopathy
KW - iPSC-derived models
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UR - http://www.scopus.com/inward/citedby.url?scp=85161815810&partnerID=8YFLogxK
U2 - 10.1186/s40035-023-00363-z
DO - 10.1186/s40035-023-00363-z
M3 - Article
C2 - 37312133
AN - SCOPUS:85161815810
SN - 2047-9158
VL - 12
JO - Translational Neurodegeneration
JF - Translational Neurodegeneration
IS - 1
M1 - 31
ER -