PUBLICATION
Ablation of the pro-inflammatory master regulator miR-155 does not mitigate neuroinflammation or neurodegeneration in a vertebrate model of Gaucher's disease
- Authors
- Watson, L., Keatinge, M., Gegg, M., Bai, Q., Sandulescu, C., Vardi, A., Futerman, A.H., Schapira, A.H.V., Burton, E.A., Bandmann, O.
- ID
- ZDB-PUB-190416-4
- Date
- 2019
- Source
- Neurobiology of disease 127: 563-569 (Journal)
- Registered Authors
- Bandmann, Oliver, Burton, Edward A., Keatinge, Marcus, Watson, Lisa
- Keywords
- Gaucher's disease, Neurodegeneration, Neuroinflammation, Parkinson's disease, Zebrafish, miR-155
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Clustered Regularly Interspaced Short Palindromic Repeats
- Cytokines/metabolism
- Disease Models, Animal
- Disease Progression
- Encephalitis/genetics
- Encephalitis/metabolism*
- Encephalitis/pathology
- Gaucher Disease/genetics
- Gaucher Disease/metabolism*
- Gaucher Disease/pathology
- Glucosylceramidase/genetics
- Glucosylceramidase/metabolism
- Mice
- MicroRNAs/genetics
- MicroRNAs/metabolism*
- Mutation
- Nerve Degeneration/genetics
- Nerve Degeneration/metabolism*
- Nerve Degeneration/pathology
- Neurons/metabolism
- Neurons/pathology
- Up-Regulation
- Zebrafish
- PubMed
- 30981829 Full text @ Neurobiol. Dis.
Citation
Watson, L., Keatinge, M., Gegg, M., Bai, Q., Sandulescu, C., Vardi, A., Futerman, A.H., Schapira, A.H.V., Burton, E.A., Bandmann, O. (2019) Ablation of the pro-inflammatory master regulator miR-155 does not mitigate neuroinflammation or neurodegeneration in a vertebrate model of Gaucher's disease. Neurobiology of disease. 127:563-569.
Abstract
Bi-allelic mutations in the glucocerebrosidase gene (GBA1) cause Gaucher's disease, the most common human lysosomal storage disease. We previously reported a marked increase in miR-155 transcript levels and early microglial activation in a zebrafish model of Gaucher's disease (gba1-/-). miR-155 is a master regulator of inflammation and has been implicated in a wide range of different neurodegenerative disorders. The observed miR-155 upregulation preceded the subsequent development of widespread pathology with marked neuroinflammation, closely resembling human Gaucher's disease pathology. We now report similar increases of miR-155 expression in mammalian models of GD, confirming that miR-155 upregulation is a shared feature in glucocerebrosidase (GCase) deficiency across different species. Using CRISPR/Cas9 mutagenesis we then generated a miR-155 mutant zebrafish line (miR-155-/-) with completely abolished miR-155 expression. Unexpectedly, loss of miR-155 did not mitigate either the reduced lifespan or the robust inflammatory phenotypes of gba1-/- mutant zebrafish. Our data demonstrate that neither neuroinflammation nor disease progression in GCase deficiency are dependent on miR-155 and suggest that miR-155 inhibition would not be a promising therapeutic target in Gaucher's disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping