PUBLICATION
Glucocerebrosidase 1 deficient Danio rerio mirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein-independent neuronal cell death
- Authors
- Keatinge, M., Bui, H., Menke, A., Chen, Y.C., Sokol, A.M., Bai, Q., Ellett, F., Da Costa, M., Burke, D., Gegg, M., Trollope, L., Payne, T., McTighe, A., Mortiboys, H., de Jager, S., Nuthhall, H., Kuo, M.S., Fleming, A., Schapira, A.H., Renshaw, S.A., Highley, J.R., Chacinska, A., Panula, P., Burton, E.A., O'Neill, M.J., Bandmann, O.
- ID
- ZDB-PUB-150918-13
- Date
- 2015
- Source
- Human molecular genetics 24(23): 6640-52 (Journal)
- Registered Authors
- Bandmann, Oliver, Burton, Edward A., Chacinska, Agnieszka, Da Costa, Marc, de Jager, Sarah, Ellett, Felix, Fleming, Angeleen, Keatinge, Marcus, Panula, Pertti, Renshaw, Steve A., Trollope, Lisa
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Death
- Disease Models, Animal*
- Gaucher Disease/genetics*
- Gaucher Disease/pathology
- Glucosylceramidase/genetics*
- MicroRNAs/genetics
- Microglia/metabolism
- Microglia/physiology
- Neurons/metabolism
- Neurons/pathology*
- Neurons/physiology
- Sequence Deletion
- Up-Regulation
- Zebrafish*/genetics
- Zebrafish*/metabolism
- Zebrafish Proteins/genetics*
- alpha-Synuclein/metabolism
- PubMed
- 26376862 Full text @ Hum. Mol. Genet.
Citation
Keatinge, M., Bui, H., Menke, A., Chen, Y.C., Sokol, A.M., Bai, Q., Ellett, F., Da Costa, M., Burke, D., Gegg, M., Trollope, L., Payne, T., McTighe, A., Mortiboys, H., de Jager, S., Nuthhall, H., Kuo, M.S., Fleming, A., Schapira, A.H., Renshaw, S.A., Highley, J.R., Chacinska, A., Panula, P., Burton, E.A., O'Neill, M.J., Bandmann, O. (2015) Glucocerebrosidase 1 deficient Danio rerio mirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein-independent neuronal cell death. Human molecular genetics. 24(23):6640-52.
Abstract
Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's Disease (GD). Heterozygous GBA1 mutations (GBA(+/-)) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity in GBA(+/-) carriers and alpha-synuclein-mediated neurotoxicity. However, it is unclear whether other mechanisms also contribute to the increased risk of PD in GBA(+/-) carriers. The zebrafish genome does not contain alpha-synuclein (SNCA), thus providing a unique opportunity to study pathogenic mechanisms unrelated to alpha-synuclein toxicity. Here we describe a mutant zebrafish line created by TALEN genome editing carrying a 23 bp deletion in gba1 (gba1(c.1276_1298del)), the zebrafish orthologue of human GBA1. Marked sphingolipid accumulation was already detected at 5 days post fertilization with accompanying microglial activation and early, sustained up-regulation of miRNA-155, a master regulator of inflammation. gba1(c.1276_1298del) mutant zebrafish developed a rapidly worsening phenotype from 8 week onwards with striking reduction in motor activity by 12 weeks. Histopathologically, we observed marked Gaucher cell invasion of the brain and other organs. Dopaminergic neuronal cell count was normal through development but reduced by>30% at 12 weeks in the presence of ubiquitin-positive, intra-neuronal inclusions. This gba1(c.1276_1298del) zebrafish line is the first viable vertebrate model sharing key pathological features of GD in both neuronal and non-neuronal tissue. Our study also provides evidence for early microglial activation prior to alpha-synuclein-independent neuronal cell death in GBA1 deficiency and suggests upregulation of miR-155 as a common denominator across different neurodegenerative disorders.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping