Modelling neurodegeneration in zebrafish

3 Nov 2016. NUS biologists have discovered a mechanism explaining why motor neurons are more vulnerable and degenerate first in a common neurodegenerative disease.

Spinal Muscular Atrophy (SMA) is the most common genetic cause of infant death and is characterised by the loss of motor neurons and muscle wasting in children and younger adults. This devastating disease is caused by mutations in Survival Motor Neuron (Smn), a protein that performs general housekeeping functions in all cells of the body. It remains an unresolved mystery in the field of neurodegeneration research on why a reduction of this essential factor causes defects almost exclusively in motor neurons but not in other cells.

Using a zebrafish model, a research team led by Prof Christoph WINKLER and his former postdoctoral fellow, Dr Zoltan SPIRO from Department of Biological Sciences, NUS discovered that motor neurons in fact have an increased demand for Smn protein. They have also identified the Etv5b protein as a novel regulator of Smn activity, which is essential for motor neuron health.

The Smn protein is active in all cells of the body and is required for the assembly of spliceosomes. Previous studies using cell culture assays or mouse models for SMA could not solve the important question of why a deficiency in Smn almost exclusively affects only motor neurons. Addressing this controversial issue of a selective vulnerability of motor neurons is now possible by using the zebrafish model, which allows live imaging of individual neuron behaviour in intact specimens.

This research has provided novel insights into the mechanism underlying neurodegeneration in SMA to understand the reasons why motor neurons are more vulnerable than other cells. Insights into these processes also provide better understanding of other types of motor neuron diseases, such as Amyotrophic Lateral Sclerosis (ALS). The finding that the Etv5b protein is responsible for generating sufficient levels of Smn could be used to develop better drugs for improving motor neuron health and therefore, the survival of SMA patients.

Although the current work has shown that motor neurons have an increased demand for the Smn protein, which in turn is controlled by the Etv5b protein, it still remains unclear why motor neurons need more Smn than other cells. Future studies could be designed to discover whether particular RNA splicing events or other motor neuron-specific processes are responsible for the increased Smn demand in motor neurons.

37. C Winkler DBS 20160907 1

Figure shows zebrafish which are popular animal models in biomedical research used to study the unknown mechanisms of numerous human diseases. Adult zebrafish females (top) produce up to 200 embryos per day. These embryos (bottom left) are transparent and develop rapidly outside the mother. Genetic tools are available to fluorescently label motor neurons, which can be visualised to study their functions and connections in healthy and diseased animals by live imaging (bottom right; image credit: Shermaine TAY).

 

Reference

Spiró Z; Koh A; Tay S; See K; Winkler C*, "Transcriptional enhancement of Smn levels in motoneurons is crucial for proper axon morphology in zebrafish" SCIENTIFIC REPORTS Volume: 6 Article Number: 27470 DOI: 10.1038/srep27470 Published: 2016