Animal-model breakthrough by successfully modelling microglia-driven leukodystrophy in zebrafish

Neurons expressing human pathological Tau (red) and microglia (green) in the zebrafish embryonic brain. Credits: Nadia Soussi-Yaniscostas
A new breakthrough in understanding the cause of rare childhood brain disorders has been made by researchers at the University of Sheffield.

The contribution of microglia in neurological disorders has long thought to be a consequence of pathology but is now emerging as a leading disease driver. Now, a genetic animal model shows an essential point in this matter.

The disease in question is Leukodystrophy.  A disease that many animal models have failed to mimic to the human counterpart successfully…until shortly.

Taking into account that some of our team-mates at ZeClinics also have been researching about hypomyelinating leukodystrophy in zebrafish (a different subtype of the disease) we are now more than pleased to see that colleagues at the University's Neuroscience Institute and Bateson Centre have achieved - not only to mimic the key-aspects of the human disease correctly by mutating the rnaset2 gene in Zebrafish - but also to shed more light on the disease-cause and the involvement of the microglia.

But first of all: What is Leukodystrophy or Leukodystrophies?

Leukodystrophies are a group of rare and progressive diseases, which have in common a resulting irregular development or/and destruction of the white matter of the brain, also known as “myelin sheath.” Each Leukodystrophy “type” known is caused by a specific gene abnormality, which affects a different part of the myelin sheath.

Even though the genetic factors or causes are known, we still know very little about the actual disease-progression and physiological reasons, which lead to this destruction, as animal models were not displaying the disease correctly until the date. It is due to this so exciting that the Zebrafish - which is evolutionary further away to humans than rodents - is now at the forefront of leukodystrophy preclinical models thanks to its high conservation of genetic key-drivers in many diseases.

Thanks to the transparency of the fish, the scientists used live imaging as well as electron microscopy to study the phenotype and identified that the mutant microglia of the model displayed an engorged morphology and was filled with undigested apoptotic cells and undigested substrate.

Likewise, the team also showed that the increased number of apoptotic cells is not due to increased neuronal cell death but to microglial failure at digesting apoptotic bodies, identifying the microglia as a potential key cellular player in the pathology of RNAseT2‐deficient leukoencephalopathy from its early stages.

Why is microglia so important?

Developmental apoptosis is critical for the formation of a healthy brain, as unhealthy or dangerous cells are removed. However, the resulting dead cells need to be cleared. The microglia are considered as a part of a necessary immune response which allows this natural clearing of neurons that suffered apoptosis.

Looking at the results, the team has hypothesized that the early onset of RNAseT2‐deficient leukoencephalopathy is caused by abnormal microglial activity during neurodevelopment, related to an upregulation of the immune system in brains, as showed by gene-expression analysis.

Most important of this breakthrough, however, is the evidence which this model provides to focus on therapies that can target the microglial population, which might finally be able to give an according weapon against this fatal disease.

By: Marina Müller, ZeClinics
Ver medio View full article EUREKALERT

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