Glucocerebrosidase 1 deficient Danio rerio mirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein-independent neuronal cell death.

Abstract

Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's disease (GD). Heterozygous GBA1 mutations (GBA1(+/-)) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity in GBA1(+/-) carriers and alpha-synuclein-mediated neurotoxicity. However, it is unclear whether other mechanisms also contribute to the increased risk of PD in GBA1(+/-) carriers. The zebrafish genome does not contain alpha-synuclein (SNCA), thus providing a unique opportunity to study pathogenic mechanisms unrelated to alpha-synuclein toxicity. Here we describe a mutant zebrafish line created by TALEN genome editing carrying a 23 bp deletion in gba1 (gba1(c.1276_1298del)), the zebrafish orthologue of human GBA1. Marked sphingolipid accumulation was already detected at 5 days post-fertilization with accompanying microglial activation and early, sustained up-regulation of miR-155, a master regulator of inflammation. gba1(c.1276_1298del) mutant zebrafish developed a rapidly worsening phenotype from 8 weeks onwards with striking reduction in motor activity by 12 weeks. Histopathologically, we observed marked Gaucher cell invasion of the brain and other organs. Dopaminergic neuronal cell count was normal through development but reduced by >30% at 12 weeks in the presence of ubiquitin-positive, intra-neuronal inclusions. This gba1(c.1276_1298del) zebrafish line is the first viable vertebrate model sharing key pathological features of GD in both neuronal and non-neuronal tissue. Our study also provides evidence for early microglial activation prior to alpha-synuclein-independent neuronal cell death in GBA1 deficiency and suggests upregulation of miR-155 as a common denominator across different neurodegenerative disorders.

• Authors: Marcus Keatinge, Hai Bui, Aswin Menke, Yu-Chia Chen, Anna M Sokol, Qing Bai, Felix Ellett, Marc Da Costa, Derek Burke, Matthew Gegg, Lisa Trollope, Thomas Payne, Aimee McTighe, Heather Mortiboys, Sarah de Jager, Hugh Nuthall, Ming-Shang Kuo, Angeleen Fleming, Anthony H V Schapira, Stephen A Renshaw, J Robin Highley, Agnieszka Chacinska, Pertti Panula, Edward A Burton, Michael J O'Neill, Oliver Bandmann
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 23 Pg. 6640-52 (Dec 01 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 26376862 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press.

Chemical References

• MIRN155 microRNA, zebrafish
• MicroRNAs
• Zebrafish Proteins
• alpha-Synuclein
• Glucosylceramidase
• gba protein, zebrafish

Topics

• Animals
• Cell Death
• Disease Models, Animal
• Gaucher Disease (genetics, pathology)
• Glucosylceramidase (genetics)
• MicroRNAs (genetics)
• Microglia (metabolism, physiology)
• Neurons (metabolism, pathology, physiology)
• Sequence Deletion
• Up-Regulation
• Zebrafish (genetics, metabolism)
• Zebrafish Proteins (genetics)
• alpha-Synuclein (metabolism)