Wednesday, 16 December 2015

A fish that spins


I am scientist working on Parkinson’s disease, a form of neurodegeneration that still has no cure. Many people use cells, mice or flies to further understand disease, but my team and I use an alternative model organism, the zebrafish. Its advantages are that unlike mice, it is transparent, so we can monitor cells in real time. It is also genetically closer to humans than other model organisms such as flies, and it is also very cost effective to house. Although we don’t know the cause of most cases of Parkinson’s disease, we know that about 5% of patients carry a single defect in a gene known as Glucocerebrosidase (GBA). What is really interesting is that when you have two faulty copies of the GBA gene it leads to a rare neurodegenerative disorder known as Gaucher’s disease. 

Gaucher’s disease, in its extreme forms, can result in neurodegeneration and death in infancy. But its symptoms are very variable and can include a wide variety of symptoms including epilepsy, blood cell problems, osteoporosis, and enlarged organs to name a few. The pathology is mainly driven by immune cells that swell up with substrates normally broken down by GBA. These swollen cells known as “Gaucher cells” accumulate in different parts of the body such as the liver, causing it to swell in size quite dramatically. 

To further understand Gaucher’s disease and how these gene defects can cause these symptoms, we made a zebrafish with a faulty GBA gene, using a new technology known as “gene editing”. This made a large deletion in the GBA gene of the zebrafish. By studying the effects of a defective GBA gene, we are hoping to further understand both Gaucher’s disease and Parkinson’s disease. 


The lack of GBA1 in Gaucher's fish (top) causes them to develop a curved spine compared to controls who produce normal amounts for GBA1 (bottom).

T
he zebrafish carrying the defective GBA gene were very striking; they initially developed normally, but by the time they reached maturity at 3 months of age, they started to spin very fast in circles as can be seen in the video below. Such a behaviour was very surprising to us, as we had never encountered it before in any other zebrafish model.

video


Gaucher’s disease mainly affects the immune system so to investigate its effects further, we bred our Gaucher’s fish with special fish that have glowing immune cells and selected offspring that have both a faulty GBA gene and fluorescing immune cells. Due to the zebrafish’s transparency, we could then monitor how these immune cells were affected by the lack of a functional GBA gene. 



The lack of GBA1 leads to inflammation in the brain: brain sections of Gaucher's fish (left) show an increase in macrophages and microglia (green) compared
to healthy counterparts (right).

This led to the discovery that our fish were already showing signs of inflammation as the immune cells were affected very early on in development at 5 days of age. By the time the fish started to spin, we found these rogue immune cells had taken over vast areas of the liver and brain. This inflammation, we believe, is being triggered by increased levels of a special inflammatory master regulator gene called Mir155. We are currently investigating the biology of this gene further to see, if it will be a suitable drug target to treat Gaucher’s disease. 


Our Gaucher’s fish was an extremely exciting mutant to study and characterise. But like all scientific adventures it was a large team effort. Our lab was fortunate to collaborate with many gifted scientists all around the world.


Reference:
Keatinge, M; Bui, H; Menke, A; Chen, YC; Sokol, AM; Bai, Q; Ellett, F; Da Costa, M; Burke, D; Gegg, M; Trollope, L; Payne, T; McTighe, A; Mortiboys, H; de Jager, S; Nuthall, H; Kuo, MS; Fleming, A; Schapira, AHV; Renshaw, SA; Highley, JR; Chacinska, A; Panula, P; Burton, EA; O'Neill, MJ and Bandmann, O. 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. Hum. Mol. Genet. 2015, 1-13; September 16 doi: 10.1093/hmg/ddv369

 
 By Dr Marcus Keatinge

Marcus is a post-doctoral researcher in Professor Oliver Bandmann's group working on Parkinson's disease and related disorders. To find our more about his research, follow him on ResearchGate. 










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