Lysosomes are ubiquitous and dynamic organelles with a central role in degradation and recycling of damaged cell components and misfolded proteins,otherwise known as autophagy.Autophagy plays a fundamental role in the...Lysosomes are ubiquitous and dynamic organelles with a central role in degradation and recycling of damaged cell components and misfolded proteins,otherwise known as autophagy.Autophagy plays a fundamental role in the process of correcting cell homeostasis and cellular survival.Unsurprisingly,this process is essential in the central nervous system,as neurons are not able to easily eliminate altered proteins given their post-mitotic state.展开更多
Lysosomes are the major degradative compartments within eukaryotic cells.Besides their role in the degradation and recycling of intra-and extracellular molecules,they further mediate important biological processes,suc...Lysosomes are the major degradative compartments within eukaryotic cells.Besides their role in the degradation and recycling of intra-and extracellular molecules,they further mediate important biological processes,such as immune signaling and perpetuation of nutrientand energy homeostasis.展开更多
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 lysosom...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.展开更多
基金supported by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)(No.125440785–SFB877,project B11)by the Interdisciplinary Center for Clinical Research(IZKF)at the University Hospital of the University of Erlangen-Nuremberg(Jochen-Kalden funding program N8)(both to FZ)。
文摘Lysosomes are ubiquitous and dynamic organelles with a central role in degradation and recycling of damaged cell components and misfolded proteins,otherwise known as autophagy.Autophagy plays a fundamental role in the process of correcting cell homeostasis and cellular survival.Unsurprisingly,this process is essential in the central nervous system,as neurons are not able to easily eliminate altered proteins given their post-mitotic state.
基金supported by the Interdisciplinary Center for Clinical Research(IZKF)at the University Hospital of the University of Erlangen-Nuremberg(JochenKalden funding programme N8)。
文摘Lysosomes are the major degradative compartments within eukaryotic cells.Besides their role in the degradation and recycling of intra-and extracellular molecules,they further mediate important biological processes,such as immune signaling and perpetuation of nutrientand energy homeostasis.
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.
文摘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.
