TY  - JOUR
TI  - Glucocerebrosidase activity, cathepsin D and monomeric ?-synuclein interactions in a stem cell derived neuronal model of a PD associated GBA1 mutation.
N1  - This work is licensed under a Creative Commons Attribution 4.0 International License. The images
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AV  - public
VL  - 134
KW  - Ambroxol
KW  -  Cathepsin D
KW  -  Cerezyme
KW  -  Glucocerebrosidase
KW  -  Monomeric ?-Synuclein
KW  -  Parkinson's disease
N2  - 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.
Y1  - 2020/02/01/
JF  - Neurobiology of Disease
ID  - discovery10084676
UR  - https://doi.org/10.1016/j.nbd.2019.104620
A1  - Yang, S-Y
A1  - Gegg, M
A1  - Chau, D
A1  - Schapira, A
ER  -