Exosomes could be critical players in the onset of Parkinson’s and other neurodegenerative disorders, says Jason Howitt
What’s the focus of your research?
For our exosome research, the main focus is Parkinson’s disease and related neurodegenerative disorders.
Parkinson’s disease is associated with the formation in the brain of misfolded clumps of a protein called α-synuclein. We’ve found a way that α-synuclein is packaged inside exosomes, and we’ve been studying how that can affect the brain to cause the disease.
The other focus we have is how exosomes work in the body in general – how they move in the body, where they can move to, and what they do.
As a neurobiologist, what first sparked your interest in exosomes?
We’ve been working on exosomes for the past decade – quite a long time for a field that is still in its infancy. When we originally started, it was a quiet area of research.
The story was, a colleague at the Florey Institute of Neuroscience and Mental Health and I were working on a protein found in the membrane of cells. He decided to do a fairly strange experiment, to see if this protein could also be found outside of the cell. In theory, being a transmembrane intracellular protein, it shouldn’t have been – but he found it was.
Straight away that meant the protein had to be released in a membrane. He started searching for what that membrane could be, and it turned out it was an exosome – the nanoscopic, membrane-wrapped packages of proteins and other biomolecules we now know most cells release. I’ve been working on exosomes, and following their story, ever since.
I must say I was very sceptical at the start about what exosomes were and whether they had any function. There’s since been a huge amount of research in vitro, in cell culture and things like that – and in the last 4 years, convincing evidence emerged that there’s a true function for exosomes inside the body.
In the last 2 years the field has really exploded and there’s been a lot of interesting studies to show that they have an important role in lots of different diseases as well as normal biological function.
What area are you working on and how do exosomes relate?
The thing with exosomes is you can look almost anywhere in the body and they’re going to be there. The question is, what are they doing there?
One theory was that exosomes were just a type of waste removal. But we really think exosomes are a form of communication between cells, for good and bad.
One of the things we’ve tried to work out is to make tools to actually follow the function of exosomes. We made a tag that’s like a barcode. Using mouse genetics you can study where the exosome has gone, where it has travelled in the body. Depending on the cell type that exosome has come from, they have different locations they like to go to.
From our work, the exosomes from cancer-like cells seem to have a bigger prevalence to communicate to more cells than the exosomes from a normal cell type from the body. That’s early studies, we still have to confirm those things, but that’s what we’ve observed so far.
And your work on Parkinson’s disease?
We are using animal models to study how α-synuclein protein is packaged inside exosomes, and how that might contribute the development of Parkinson’s.
There’s quite a bit of free α-synuclein floating around in both the blood and CSF of patients with Parkinson’s disease, but it just doesn’t seem to be effective at being taken up in cells to cause protein aggregation.
Even though exosomal α-synuclein is only a very small component of the α-synuclein released in the brain, maybe 5% of the total, it’s the component that can probably cause disease, that’s what we’re working on.
It’s very exciting but I can’t say much more at the moment. We hope to be submitting a paper on our research soon.
How do you hope your research will have a medical benefit?
In terms of neurodegenerative diseases, it’s contributing to a better understanding of the initial events that lead to Parkinson’s or Alzheimer’s.
The events that first seed the aggregation of problematic proteins like α-synuclein in the brain is really critical to find out – and at the moment, there’s not a lot of information on what causes or starts these diseases.
The next step, actual applications towards inhibiting these diseases – that’s really tricky. There are already some drugs that can inhibit the release of exosomes, and they work really well in animal models, so there is a chance you could start to inhibit the release. But as for the timing and when you would use these drugs, I think that’s going to be hard to work out.
One idea is that receiving a head injury or something like that could be a trigger for neurodegeneration down the line – so might you give a drug after head injury?
Another possibility is that the seed for neurodegeneration happens in the periphery of the body, and it is exosomes that carry it into the brain. If that’s the case, there is the potential for inhibiting it. Prehaps you can flush your system of exosomes – dialysis is one way – but that may be a bad thing as well as a good thing as you would flush out beneficial exosomes as well as harmful ones. But for now, we just don’t know enough about that sort of aspect of the disease.
How have you been interacting with Exopharm?
Exopharm initially got in touch because they were just interested in understanding exosomes more. Because we’ve been working with exosomes for a while, we’ve certainly gone through the ‘this doesn’t work, this does work’ phase.
And the relationship has just developed from there. We are now helping characterise some of the prototype materials they are making using their LEAP exosome purification technology.
Historically it has been very hard to purify exosomes – so the notion you can make a lot of them of a certain grade I think is really important. That’s the promise of their technology. To have that sort of potential is really important.
In terms of research, we have some big exosome experts in Melbourne already, so it’s really exciting to have a company commercialising aspects of exosomes in the same place, where some of the major research in exosomes is happening. There’s a good synergy there.
You’ve worked in the exosomes area for 10 years now – where do you think the field will be in another 10 years?
In the last 5 or so years, exosome research has really accelerated – and there’s a lot more to come out of this area.
Definitely for diagnostics, there are some really clear pathways for exosomes to be used in lots of different diseases and medical treatments.
Right now I think the key hurdles are understanding the different types of exosomes, and much more about the surface receptors they have that enable them to go to the correct location.
That will encompass engineering exosomes so that you can actually target specific tissues, which people are definitely trying to do now. And then creating designer exosomes to package and deliver substances that we would like to do.
One of the great things about exosomes is the way they have of making things bioavailable. A drug that may not cross the blood-brain barrier, or even across the placenta, for example. But exosomes seem able to cross almost any barrier and get almost anywhere you like. For the delivery of therapeutics it’s pretty clear they have potential.
In 10 years time I hope to see exosomes being used as therapeutics, as well as diagnostics, for a number of disorders.
Further reading – Jason’s “coolest paper” (so far)
– Sterzenbach U, Putz U, Low L-H, Silke J, Tan S-S, Howitt J. Engineered exosomes as vehicles for biologically active proteins. Mol Therp. 2017, Jun 7;25(6):1269-1278.