Blog – Fading stars: disorder in the galaxy of the brain

There are more connection points (synapses) between our brain cells than there are stars in our galaxy. These tiny structures are essential for brain function and hold the key to our every thought, feeling, movement and memory. Given their fundamental role in brain function, it is maybe unsurprising that their dysfunction is linked to many diseases of the brain. But where, when, and why do these connections break down and can we find ways of stopping it? This is essentially the focus of my research team at the University of Dundee. In this blog post I will summarise how synapse loss is a conserved feature across two seemingly different diseases: Frontotemporal Dementia (FTD) and Motor Neuron Disease (MND).

FTD hit the headlines recently when Bruce Willis announced his formal retirement from acting, following diagnosis of FTD. It is a rarer form of dementia than Alzheimer’s disease (AD), most commonly diagnosed between 45-65 years of age and is caused by disruption in the frontal and temporal lobes. People living with FTD often display changes in personality, mood, and language, with memory problems usually occurring later.

How could this possibly have any link to Motor Neuron Disease, which only causes movement problems, right?

MND is gaining a lot of exposure thanks to a few high-profile sportsmen living with the disease, and superhero endurance feats by their close family and friends to raise money for MND care and research. Rob Burrow, his wife Lindsey, and their close friend Kevin Sinfield recently ran the London marathon to raise awareness and funds for MND and often appear on TV to talk about their lived experience. MND is an umbrella term for several diseases caused by the breakdown of the motor neurons in the brain and/or spinal cord. This leads to progressive weakening of the muscles and paralysis, with many passing away within two to three years after diagnosis. However, around half of all MND patients also have problems with their thinking skills and show changes that are very similar to people with FTD, mostly language, personality, and mood changes. This is very important because these changes are often over-looked yet can have a profound impact on the quality of life of the patient and their support network and these patients tend to have a more aggressive form of disease.

Could similar underlying changes in the brain explain the similar symptoms in FTD and MND?

We know that synapse loss is the strongest correlate with cognitive decline in AD, and that synapse loss occurs in the brains of people with FTD. This was shown in several studies during the 1990’s that linked synapse density in post-mortem human brains with previous cognitive testing scores. Functional and structural brain scanning of MND patients with and without cognitive decline revealed changes in parts of the frontal cortex, that looked like changes observed in people with FTD. However, we had no idea what the underlying changes were that associated with cognitive change. Therefore, as a PostDoc in the lab of Prof. Tara Spires-Jones in Edinburgh, I started looking at this with the hypothesis that synapse loss could be a major feature. Synapse loss had never been linked to cognitive change in MND before and I was fortunate that MND Scotland found my hypothesis compelling enough to award me a 3yr project grant in 2016. Using two high-resolution imaging techniques, I discovered that MND patients tended to have a lower synapse density in the frontal cortex than people without MND. Importantly, MND patients with cognitive decline tended to have the lowest synapse densities, suggesting a link for the first time between cognitive change in MND and synapse loss. Interestingly, this looks to have been confirmed in recent work using live human participants and synapse-targeting tracers which can be visualised in a PET scan. The researchers found that synapse loss in the frontal cortex of FTD patients tracked closely with progressive cognitive decline.

Chris works with MND Scotland, who are a significant funder of MND Research. See their grant calls at https://bit.ly/46iFzVy

So what is driving synapse loss?

It is becoming increasingly accepted across the neurodegeneration field that synapse loss is a central player in disease. However, the mechanisms driving synapse loss are largely unknown. Following my previous work showing that synapse loss occurs in the frontal cortex of MND patients with cognitive decline, we decided to perform experiments to try and discover why they were being lost. We extracted synaptically-enriched fractions from post-mortem brain and isolated the proteins for identification by mass-spectrometry. We had three groups, non-neurological controls, MND and MND with cognitive impairment. We identified almost 6000 proteins at the synapse and found several hundred changed in expression in the MND samples. Importantly, based on our experimental approach we could tease out a molecular signature that was present in the MND with cognitive impairment samples. This revealed key inflammatory pathways that were upregulated and several postsynaptic scaffolding proteins that were downregulated. One of the inflammatory pathways we identified has already been linked to a shorter survival time in MND patients. We are now working on whether these changes are cause or consequence of disease and whether some of these changes are specific for MND or merely a feature of end-stage neurodegenerative disease.

What about disease-associated proteins at the synapse?

In both of my studies described above, I also showed that a protein linked with Alzheimer’s, FTD and MND called TDP-43, was found to be present at the human synapse. TDP-43 is normally found in the nucleus, but around 30% is thought to exist outside the nucleus in other cellular locations, such as the synapse. Could disfunction in this protein be a link between several diseases of the brain? To try and get at this question MND Scotland and Alzheimer’s Research UK recently funded a collaborative project between myself and Dr. Francisco Inesta-Vaquera in Dundee, to establish new model systems for assessing TDP-43-induced cell stress. While this project will not be able to address synaptic roles for TDP-43 pathology, it will generate novel temporal and spatial information on the development of TDP-43-induced damage in the brain. This will be important for many brain diseases, given the convergent accumulation of TDP-43 pathology. Further work in our lab is now focussing on the synaptic role of TDP-43 and whether this may be a more direct link between pathology, synapse loss and overlapping cognitive decline in AD, FTD and MND.

Working together

I believe it’s very important for different funders to work together and look at some of the commonalities between different diseases. AD, FTD and MND are different diseases, they mostly affect different brain areas, different cell types are particularly vulnerable, clinical presentation is predominantly distinct but there is a lot to learn in the areas of overlap. Furthermore, and most importantly, by working in these areas of overlap any breakthrough in understanding will have far-reaching impact across diseases.

As we advance our understanding of brain disease, I hope one day we will be able to ensure that everyone’s galaxy shines bright into old age.

Dr Christopher Henstridge

Author

Dr Chris Henstridge is a Principle Investigator at University of Dundee. Chris studies anatomical and molecular changes in the human synapse, with a particular focus on Motor Neuron Disease (MND). Chris grew up on the far north coast of Scotland and that beautiful location instilled his interest in nature and biology. He completed his PhD in Dundee, then spent time in Budapest and other parts of Scotland, before returning to Dundee to establish his own lab.

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