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Neurobiol Dis. 2019 Apr 11;127:563-569. doi: 10.1016/j.nbd.2019.04.008. [Epub ahead of print]

Ablation of the pro-inflammatory master regulator miR-155 does not mitigate neuroinflammation or neurodegeneration in a vertebrate model of Gaucher's disease.

Author information

1
The Bateson Centre, University of Sheffield, Sheffield, UK; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
2
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
3
Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, USA.
4
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
5
The Bateson Centre, University of Sheffield, Sheffield, UK; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK. Electronic address: o.bandmann@sheffield.ac.uk.

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.

KEYWORDS:

Gaucher's disease; Neurodegeneration; Neuroinflammation; Parkinson's disease; Zebrafish; miR-155

PMID:
30981829
DOI:
10.1016/j.nbd.2019.04.008
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