Watson, L., Keatinge, M., Gegg, M. et al. (7 more authors) (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. pp. 563-569. ISSN 0969-9961
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.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2019 Published by Elsevier Inc. |
Keywords: | Gaucher's disease; Neurodegeneration; Neuroinflammation; Parkinson's disease; Zebrafish; miR-155; Animals; Animals, Genetically Modified; Clustered Regularly Interspaced Short Palindromic Repeats; Cytokines; Disease Models, Animal; Disease Progression; Encephalitis; Gaucher Disease; Glucosylceramidase; Mice; MicroRNAs; Mutation; Nerve Degeneration; Neurons; Up-Regulation; Zebrafish |
Dates: |
|
Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection, Immunity and Cardiovascular Disease |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL MR/R011354/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 28 Feb 2023 15:51 |
Last Modified: | 28 Feb 2023 15:51 |
Status: | Published |
Publisher: | Elsevier |
Refereed: | Yes |
Identification Number: | 10.1016/j.nbd.2019.04.008 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:196865 |