Loss of glucocerebrosidase 1 activity causes lysosomal dysfunction and alpha-synuclein aggregation
Experimental & Molecular Medicine
;
: e153-2015.
Article
in English
| WPRIM
| ID: wpr-57313
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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Protein Binding
/
Cell Line
/
Zinc Fingers
/
Gene Order
/
Enzyme Activation
/
Alpha-Synuclein
/
Gene Knockout Techniques
/
Genetic Loci
/
Protein Aggregation, Pathological
/
Glucosylceramidase
Type of study:
Etiology study
/
Risk factors
Limits:
Humans
Language:
English
Journal:
Experimental & Molecular Medicine
Year:
2015
Type:
Article
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