Dataset Information

Glucocerebrosidase activity, cathepsin D and monomeric ?-synuclein interactions in a stem cell derived neuronal model of a PD associated GBA1 mutation.

ABSTRACT: The presence of GBA1 gene mutations increases risk for Parkinson's disease (PD), but the pathogenic mechanisms of GBA1 associated PD remain unknown. Given that impaired ?-synuclein turnover is a hallmark of PD pathogenesis and cathepsin D is a key enzyme involved in ?-synuclein degradation in neuronal cells, we have examined the relationship of glucocerebrosidase (GCase), cathepsin D and monomeric ?-synuclein in human neural crest stem cell derived dopaminergic neurons. We found that normal activity of GCase is necessary for cathepsin D to perform its function of monomeric ?-synuclein removal from neurons. GBA1 mutations lead to a lower level of cathepsin D protein and activity, and higher level of monomeric ?-synuclein in neurons. When GBA1 mutant neurons were treated with GCase replacement or chaperone therapy; cathepsin D protein levels and activity were restored, and monomeric ?-synuclein decreased. When cathepsin D was inhibited, GCase replacement failed to reduce monomeric ?-synuclein levels in GBA1 mutant neurons. These data indicate that GBA1 gene mutations increase monomeric ?-synuclein levels via an effect on lysosomal cathepsin D in neurons.

SUBMITTER: Yang SY

PROVIDER: S-EPMC6983928 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Glucocerebrosidase activity, cathepsin D and monomeric α-synuclein interactions in a stem cell derived neuronal model of a PD associated GBA1 mutation.

Yang Shi-Yu SY Gegg Matthew M Chau David D Schapira Anthony A

Neurobiology of disease 20191018

The presence of GBA1 gene mutations increases risk for Parkinson's disease (PD), but the pathogenic mechanisms of GBA1 associated PD remain unknown. Given that impaired α-synuclein turnover is a hallmark of PD pathogenesis and cathepsin D is a key enzyme involved in α-synuclein degradation in neuronal cells, we have examined the relationship of glucocerebrosidase (GCase), cathepsin D and monomeric α-synuclein in human neural crest stem cell derived dopaminergic neurons. We found that normal acti ...[more]

PMID: 31634558

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Project description:Variants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson's disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous in vitro studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Here, we conducted genetic analyses of the association between common and rare CTSB variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines and induced pluripotent stem cell-derived dopaminergic neurons and assessed lysosomal activity and the handling of aggregated synuclein fibrils. We find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by GBA1) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. These results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.

Dataset Information

Glucocerebrosidase activity, cathepsin D and monomeric ?-synuclein interactions in a stem cell derived neuronal model of a PD associated GBA1 mutation.

Publications

Glucocerebrosidase activity, cathepsin D and monomeric α-synuclein interactions in a stem cell derived neuronal model of a PD associated GBA1 mutation.

Similar Datasets

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