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.
Highlights
MiR-155 is a typical multifunctional miRNA which is involved in a wide range of different immune and inflammatory processes (Faraoni et al, 2009)
To determine whether miR-155 levels were elevated in other zebrafish models of neurodegeneration, we analysed miR-155 levels in the brains of adult pink1 deficient zebrafish (Flinn et al, 2013)
We showed that miR-155 was upregulated in three vertebrate models of GCase deficiency: gba1−/− zebrafish, Gbaflox/flox; Nestin-Cre mice, and mouse BV2 microglia treated with CBE, a GCase inhibitor
Summary
MiR-155 is a typical multifunctional miRNA which is involved in a wide range of different immune and inflammatory processes (Faraoni et al, 2009). Genetic ablation of miR-155 ameliorated disease severity and prolonged survival in SOD1G93A mice, a widely used rodent model of MND. Treating SOD1G93A mice with anti-miR-155 at the beginning of disease onset improved the disease phenotype and prolonged the lifespan, suggesting that miR-155 could be a therapeutic target for human MND (Butovsky et al, 2015). In post-mortem studies of PD patient brains, activated microglia and increased concentrations of pro-inflammatory cytokines have been identified within the substantia nigra (Boka et al, 1994; McGeer et al, 1988). An increase in pro-inflammatory cytokines in both PD patient serum and cerebrospinal fluid (CSF) has been reported (Dobbs et al, 1999; Mogi et al, 1994). Genetic studies of risk factors for PD and epidemiological studies support the role of inflammation in PD (Kaur et al 2017). miR-155 is significantly upregulated in the substantia nigra pars compacta
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