Disorders of the Nervous System

The central nervous system (CNS) coordinates the activity of the body. It includes the brain and spinal cord. 

Disorders of the CNS are severely debilitating and sufferers can be affected in many profoundly different ways, such as:

  • Control of physical movement - ranging from a reduction to a complete loss of control
  • Alteration of mood
  • Change in sociability
  • Absence of or decline in communication and reasoning skills
 The transparent nature of the zebrafish embryo enables visualisation of the developing nervous system in exquisite detail.

Neurological Disorders

A complete list of neurological disorders would run to many pages, but some of the ones we can model in zebrafish are:

  • Hereditary Spastic Paraplegia
  • Parkinson’s Disease
  • Huntington’s Disease
  • Motor Neuron Disease
  • Multiple Sclerosis

The diseases listed above typically arise during late adulthood and are progressively disabling, causing patients to lose control of voluntary movement and sometimes develop distressing involuntary physical tremors.  Because they get worse over time, they are called neurodegenerative disorders. There is no cure for any of them, and any treatment only slows the progression of symptoms or merely lessens the discomfort caused by the symptoms.

Studying CNS diseases in Sheffield

At the CDBG in Sheffield we focus on Hereditary Spastic Paraplegia (HSP) and Parkinson's Disease (PD)

HSP is a group of genetic disorders that cause progressive spasticity of the lower limbs. The involuntary muscle contractions are caused by degeneration of nerves in the spinal cord that are involved in transmitting signals from the brain to leg muscles that control their contraction and relaxation. The degeneration of these nerves in HSP therefore causes a communication breakdown leading to muscle weakness and spasticity.

  An extensive cellular scaffold, made up of microtubule networks within neurons, defines the architecture of the spinal cord in zebrafish embryos (A). Loss of spastin function in zebrafish (B) causes catastrophic breakdown of these microtubule networks in the developing spinal cord.

PD is characterised by tremor, muscle rigidity, a slowing of physical movement, and can also cause cognitive and mood disturbances. The symptoms are the result of a loss of nerve cells in part of the brain known as the substantia nigra. These cells are called dopaminergic neurons as they produce the neurotransmitter, dopamine, which is used to send messages to the parts of the brain that co-ordinate movement. When around 80% of the dopaminergic neurons are lost, the symptoms of PD start to show. The causes of PD is not absolutely clear; there are some mutations associated with the loss of dopaminergic neurons and it is thought that some toxins may also cause the disease.

Psychiatric disorders

Psychiatric disorders such as schizophrenia and bipolar disorder gradually develop during adolescence, and their symptoms also progressively worsen into adulthood.  How or why they develop is not well understood. There are changes to some genes that are known to be associated with each disorder, but there are also many environmental factors involved.

Genetic and Environmental causes of CNS disease

Although some diseases such as Huntingdon’s disease are completely genetic – a person with the mutated copy of the gene will almost certainly develop the disease – for most neurodegenerative disorders it is not that simple.

Having a certain version of a gene (such as variants of Disc1 in schizophrenia) can be associated with a disorder – frequently meaning you’re more likely to develop the disease with that particular gene variant. Sometimes, to add to the confusion, a number of different genes can influence each other resulting in a cumulative genetic risk of developing the disease.

 

Two GFP-labelled neurones in the developing zebrafish brain each have a long cell process called an axon, both of which in this case are growing towards the same target cell population.

 

Enviromental factors may also influence an individual's susceptibility to developing a disease. For example exposure to certain toxins or chemicals has been linked to the development of Parkinson’s disease.  

Studying Neurodegenerative Disorders in Fish

The zebrafish brain and spinal cord are very similar to a human’s.  They develop in much the same way and require almost identical genes to make them.

The genetic basis for some CNS diseases is only just beginning to be understood, and we can use zebrafish to understand much more about what goes wrong when particular genes are mutated. 

But zebrafish can be even more useful, because we can use the fish to find new genes and then explore their rolse in human disease.

Another important use of zebrafish is to look at the effect of environmental factors, such as chemicals and toxins on the development of neurodegenerative diseases. 

 

Links to  patient support websites:

The Motor Neurone Disease Association

The HSP/FSP Support Group

Spastic Paraplegia Foundation

The Parkinson's Disease Society 

The Huntington's Disease Association

The MS Society

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