NeuRA Magazine #20

DR NIC DZAMKO

Dr Nicolas Dzamko works with Prof Glenda Halliday to understand the causes of Parkinson’s disease. He has recently published two landmark studies that provide hope for early detection and possible treatment of Parkinson’s disease. He tells us more about the two studies.

Your first study has looked at one of the key causes of Parkinson’s disease. What did you find?
We modelled the early stages of Parkinson’s disease so we could gain a better idea of its causes and a possible treatment. This is the result of four years’ worth of work, and we’re really excited by the study’s outcomes. We’ve shown how inflammation within the brain is related to the development of Parkinson’s disease, and we’ve identified a potential mechanism that can prevent this inflammation. This gives us a new target for therapeutic research, which we’re now working on.

You’ve used a new approach for this study. Tell us about that.
This is the first time we’ve used the human-induced pluripotency stem cell model. This was the Nobel-prize winning discovery from a couple of years ago and we’ve got it up and running now, so we can take someone’s skin cells, turn them into brain cells and study them in a dish.

One of the key causes of Parkinson’s is the accumulation, or ‘clumping’, of α -synuclein in the brain, which causes a loss of cells and eventually leads to the symptoms of Parkinson’s. You were able to stop that process in your study.
Yes, that’s what we were able to do. We could activate the inflammatory pathways, see the α -synuclein clumping and introduce drugs in order to stop that from happening. Given that we were able to find this association in the post-mortem brain tissue, then model this relationship in tissue culture, we’re confident that we’ve understood a key process in the development of Parkinson’s.

What happens next?
The next stage will be to identify a drug that can be used in human trials, which acts on the pathway we’ve identified and prevents the increase in α-synuclein.

You’ve been working on a second study that has found a possible early indicator of Parkinson’s, is that correct?
We conducted one of the largest post-mortem brain studies in the world, and confirmed that a protein (LRRK2) associated with the development of Parkinson’s disease is increased in the pre-symptom stages. This leads us to believe that we may be able to treat Parkinson’s disease sooner.

What is the LRRK2 gene?
This is a gene that is found in people with a family background of Parkinson’s disease and is a known genetic contributor. The study found that there are increased levels of LRRK2 in the pre-symptomatic stages of Parkinson’s, suggesting that this may be an appropriate time to administer pharmaceutical therapies. Previous studies have shown that Parkinson’s-associated genetic mutations increase the activity of LRRK2, and that this activity can be reduced by drug therapies.

How did this collaboration come about?
The Michael J Fox Foundation got in touch with Prof Glenda Halliday and myself because we have access to brain tissue. We collaborated with the who’s who in the world of studying post-mortem brain tissue. Most of these types of studies use a sample size of eight to 12 brains. We’ve got up to 30 for each of our groups and we’ve studied not just one part of the brain, but several parts of that brain that are affected differently in the disease. So we have a really comprehensive picture of what is happening with the LRRK2 protein.

 

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The majority of adults without a mental illness still experience poor mental health, indicating a need for a better understanding of what separates mental wellness from mental illness. One way of exploring what separates those with good mental health from those with poor mental health is to use electroencephalography (EEG) to explore differences in brain activity within the healthy population. Previous research has shown that EEG measures differ between clinical groups and healthy participants, suggesting that these measures are useful indicators of mental functioning. Miranda Chilver’s current project aims to examine how different EEG measures relate to each other and to test if they can be used to predict mental wellbeing. Furthermore, she hopes to distinguish between EEG markers of symptoms including depression and anxiety, and markers of positive symptoms of wellbeing to better understand how wellbeing can exist independently of mental illness. This will be done by obtaining measures of wellbeing and depression and anxiety symptoms using the COMPAS-W and DASS-42 questionnaires, respectively. Because EEG measures and mental wellbeing are both impacted by genetics as well as the environment, Miranda will also be testing whether the links found between EEG activity and Wellbeing are driven primarily by heritable or by environmental factors. This information will inform the development of future interventions that will aim to improve wellbeing in the general population. To achieve these goals, the project will assess the relationship between EEG activity and wellbeing, and between EEG and depression and anxiety symptoms to first test whether there is an association between EEG and mental health. Second, the heritability of the EEG, wellbeing, depression, and anxiety will be assessed to determine the extent to which these variables are explained through heritable or environmental factors. Finally, a model assessing the overlap between the heritable versus environmental contributions to each measure will be developed to assess whether genetics or environment drive the relationship between EEG and mental health. This project is based on a sample of over 400 healthy adult twins from the Australian TWIN-E study of resilience led by Dr Justine Gatt. This research will pave the way for improved mental health interventions based on individual needs.
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