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

卷:127

Article

Watson, Lisa^1,2  Keatinge, Marcus^1,2  Gegg, Matthew³  Bai, Qing^4,5  Sandulescu, M. Cosmin^4,5  Vardi, Ayelet⁶  Futerman, Anthony H.⁶  Schapira, Anthony H. V.³  Burton, Edward A.^4,5  Bandmann, Oliver^1,2 

[1] Univ Sheffield, Bateson Ctr, Sheffield, S Yorkshire, England

[2] Univ Sheffield, Sheffield Inst Translat Neurosci SITraN, Sheffield, S Yorkshire, England

[3] UCL Queen Sq Inst Neurol, Dept Clin & Movement Neurosci, London, England

[4] Univ Pittsburgh, Sch Med, Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA USA

[5] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA

[6] Weizmann Inst Sci, Dept Biomol Sci, Rehovot, Israel

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

DOI  :  10.1016/j.nbd.2019.04.008

来源: Elsevier

【 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.

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