What are synapses and how much do we know about them?
Synapses are the sites that connect neurons – sites where information is passed from one neuron to another. They are highly specialized structures and synaptic function is crucial for normal brain function.
We need synapses to regulate a variety of functions, ranging from learning and memory through to locomotion, the coordination of movements such as walking.
There are over a hundred billion synapses in the brain. Importantly, there is a loss of synapses in the early stages of neurodegenerative diseases and we suspect that this is what causes symptoms to appear.
We know a lot about the formation of synapses and how the synaptic terminal of one neuron passes information to the receiving terminal of another neuron. We know which proteins are present and which ones act as the sensors of the molecule that will transmit information.
Image credit: Dr Galli / Parkinson’s UK
We know how the molecules are sending information, whether it be glutamate for excitatory synapses, dopamine for modulatory synapses or GABA for inhibitory synapses, for example. We know there is a variety of synapses that will either increase or stop the signal passing from one neuron to another.
However, we know very little about the how synapses are maintained in the older brain. Most of the studies have used developing organisms, meaning we know a lot about what happens in the early stages of development, but very little about what happens in the older brain, which is where our studies are relevant.
Please can you explain how the death of synapses contributes to Parkinson’s?
It is difficult to say exactly how the loss of synapses contributes to Parkinson's because there is no way we can detect Parkinson's during the early stages. By time patients are diagnosed, 60% to 80% of the neurons are already dead and the disease is already in the late stages.
Some cases of Parkinson’s disease have a genetic component, and from animal studies that mimic the genetic deficit that occurs in PD we now know a functional deficit and loss of the synapses occurs before the neurons die. In addition, this loss of synapses occurs together with the manifestation of motor symptoms, and therefore we think that synapses could cause the symptoms to appear.
We believe that this deficit in synapses occurs in the early stages of Parkinson's disease, something that is already known to happen in other neurological diseases such as Alzheimer's disease and Huntington's disease. However, in those diseases, we can detect and predict which patients are going to develop the illness, meaning we can study what happens early on in the disease.
We believe the loss of synapses is the cause of symptoms such as movement disorders in Parkinson's disease and the impaired cognition and memory seen in Alzheimer's, for example.
What did your recent research reveal about the death of synapses in the brain?
In our study, we show that there is a protein called Dkk1, which blocks the activity of very important proteins called Wnts, which are present in the brain. When we blocked Wnt proteins, the death of synapses occurred. This was accompanied by an impairment of motor coordination.
We could see from our studies that the animals’ coordination of movement was affected. When we put them on an accelerated cylinder, they fell from the cylinder more quickly than normal animals did.
The deficits in synapses went hand-in-hand with the deficits in motor coordination, and the deficit in synapses was caused by a deficiency in the activity of Wnt proteins. We think that during the early stages of Parkinson's, the Wnt proteins might be affected.
Would restoring Wnt’s protective abilities in people with Parkinson’s stop synapses dying and thereby the condition progressing?
We are hoping that is the case, but it still needs to be proved. In the next stage of our research, we are going to evaluate brains from Parkinson's patients and assess whether the level of Wnt proteins is altered. That will indicate whether what we have observed in the mice may also apply to Parkinson's patients.
If that is the case, we will test our hypothesis in animal models of Parkinson's disease and try to restore Wnt signalling in those animals to see if the synapses are recovered and symptoms improve. It's an exciting possibility.
How was this research funded?
Professor Patricia Salinas, head of our lab at University College London, was awarded a grant to help carry out this research from Parkinson's UK.
The European Union also supported this work, and some of the team receive funding from the MRC.
Why have researchers only just started looking at synapses in Parkinson’s research?
The main reason is because we cannot predict who is going to develop Parkinson's disease, meaning we cannot find out what happens early on in the disease. By time patients are diagnosed, the disease is quite advanced and there is already a massive neuronal loss.
However, after realising that there is a lack of dopamine in the striatum following neuronal death we looked at the genes that are linked to Parkinson's disease and what those genes do to the system. Only then did we realize that those genes actually play a role in synaptic function.
Until recently, it's been difficult to know whether synapses were affected in the early stages.
What are the next steps in this research?
As we already have the patients’ samples, we are going to evaluate several Wnt proteins to see if they are altered, because that would corroborate our hypothesis.
We are also going to assess whether Wnt signalling is affected in other animal models of Parkinson's disease, such as mice overexpressing alpha-synuclein, one of the genes that have been linked to familial PD. Then we're going to restore the activity of Wnt proteins, to try and recover the synapses and ameliorate the symptoms.
In the long term, we would like to see whether recovering or protecting synapses can slow down the progression and death of neurons. I think that if we really can ameliorate the symptoms, that would be a huge step.
What do you think will be the main hurdles that need to be overcome?
I think that the main hurdle is the fact that we cannot diagnose patients early on. Let's say we found a way of protecting synapses in the early stages, we would still need to find a way of detecting the disease in its early stages.
However, if it's true that Wnt signalling is involved in the loss of synapses during the early stages, then these molecules could be used as biomarkers, which is another important projection.
Where can readers find more information?
Deficient Wnt signalling triggers striatal synaptic degeneration and impaired motor behaviour in adult mice. Galli S et al. Nature Communications. October 2014.
For more information, and to help Parkinson’s UK in their search for a cure, visit parkinsons.org.uk/research
About Dr Soledad Galli
Dr Soledad Galli is a Parkinson’s UK funded research associate in Professor Patricia Salinas’ lab at University College London (UCL).
Soledad obtained both her MSc (Molecular Biology) and PhD (Biochemistry) at the University of Buenos Aires. From there, Soledad got a post-doc position at the Max Planck Institute in Germany where she specialized in cellular signalling and fluorescence microscopy.
In 2009 Soledad joined the laboratory of Professor Salinas at UCL which has been supported with funding from Parkinson’s UK since 2012. Soledad’s current research is focused on an area of the brain called the striatum, which is important in Parkinson’s disease. She hopes her research will lead to better ways to identify Parkinson’s early, and new treatment approaches for the condition.
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