Loss of glucocerebrosidase 1 activity causes lysosomal dysfunction and alpha-synuclein aggregation.
- Author:
Eun Jin BAE
1
;
Na Young YANG
;
Cheolsoon LEE
;
He Jin LEE
;
Seokjoong KIM
;
Sergio Pablo SARDI
;
Seung Jae LEE
Author Information
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- MeSH: Cell Line; Enzyme Activation/genetics; Gene Knockout Techniques; Gene Order; Genetic Loci; Glucosylceramidase/genetics/*metabolism; Humans; Lysosomes/*metabolism; Mutation; *Protein Aggregation, Pathological/genetics; Protein Binding; Zinc Fingers; alpha-Synuclein/chemistry/*metabolism
- From:Experimental & Molecular Medicine 2015;47(3):e153-
- CountryRepublic of Korea
- Language:English
- Abstract: Lysosomal dysfunction is a common pathological feature of neurodegenerative diseases. GTP-binding protein type A1 (GBA1) encodes beta-glucocerebrosidase 1 (GCase 1), a lysosomal hydrolase. Homozygous mutations in GBA1 cause Gaucher disease, the most common lysosomal storage disease, while heterozygous mutations are strong risk factors for Parkinson's disease. However, whether loss of GCase 1 activity is sufficient for lysosomal dysfunction has not been clearly determined. Here, we generated human neuroblastoma cell lines with nonsense mutations in the GBA1 gene using zinc-finger nucleases. Depending on the site of mutation, GCase 1 activity was lost or maintained. The cell line with GCase 1 deficiency showed indications of lysosomal dysfunction, such as accumulation of lysosomal substrates, reduced dextran degradation and accumulation of enlarged vacuolar structures. In contrast, the cell line with C-terminal truncation of GCase 1 but with intact GCase 1 activity showed normal lysosomal function. When alpha-synuclein was overexpressed, accumulation and secretion of insoluble aggregates increased in cells with GCase 1 deficiency but did not change in mutant cells with normal GCase 1 activity. These results demonstrate that loss of GCase 1 activity is sufficient to cause lysosomal dysfunction and accumulation of alpha-synuclein aggregates.
