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

Marcus Keatinge¹  Qing Bai¹  Edward A. Burton²  Anthony H.V. Schapira²  Oliver Bandmann³  M. Cosmin Sandulescu³  Ayelet Vardi⁴  Anthony H. Futerman⁴  Lisa Watson⁵  Matthew Gegg⁵ 

[1] Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK;Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel;Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK;Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, USA;The Bateson Centre, University of Sheffield, Sheffield, UK;

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

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown