Our resident blogger spoke to Professor Tiago Outeiro about his work in the field of neurodegeneration at the last German Neuroscience Society National Meeting in March. Professor Outeiro leads a team at the University of Goettingen Medical School, Germany, in the Department of Neurodegeneration and Restorative Research…
Tiago Outeiro, Professor of Neurodegeneration at the University of Goettingen Medical School.
Currently, neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s are the focus of Tiago Outeiro’s lab. I ask what led him to study such a huge scope of neurodegeneration, where most focus on just one disease; he explains that the common thread linking these diseases together is his main concern…
“I became interested in the field of neurodegeneration in the 90s when people were still talking about ‘mad cow disease’.” He begins, using the lay term for the disease at the heart of the bovine spongiform encephalopathy (BSE) scare of the 80s and 90s, which often umbrellas the human Creutzfeldt jakob diseases (CJDs) too — though only variant CJD is passed from cow to human.
“At that time the disease mechanisms of BSE and CJD were not very clear; it was known that they were neurodegenerative, characterized by the loss of certain types of brain cells, and related to protein aggregation. It was very intriguing to find that the ‘infectious’ agent causing these types of diseases was in fact a protein.” A nod towards the still perplexing subject of prion proteins, which are infectious and destructive when misfolded, but seemingly vital for cellular function when intact.
He explained the significance of this: “It was a completely new agent; it was not a bacteria or a virus – but it was infectious and transmissible. So, as a graduate student, I was very interested in the study of prions. From there things just evolved and I started studying other proteins that would also misfold and aggregate. I began working on Parkinson’s and Alzheimer’s and Huntington’s disease – that’s how it started.”
Though the protein suspects in each disease line-up may differ, they seem to have aggregation — and now propagation — mechanisms in common. So what is the current understanding of the roles such mechanisms play in neurodegenerative diseases? Outeiro describes how aggregation in particular might not be contributing to neurodegeneration as one would think…
“The majority of the diseases I study have been acknowledged for some time, some of them for more than a hundred years. One of the earliest pathological observations doctors and researchers made in studying them was the presence of protein inclusions — clumps of aggregated protein — sitting either inside or just outside neurons in diseased brains. At the time people said, ‘Okay, these big protein clumps must be doing something very bad to the cells — they are the root of the disease.’” And as the science textbooks show, the main thrust of neurodegeneration research ran with this hypothesis.
“Over time, a lot of research has brought us the current view that maybe the protein aggregates, the big clumps that we see, are not actually the disease perpetrators — aggregation may be a protective mechanism the cell has evolved in an attempt to get rid of toxic protein species.” These toxic species are the things causing damage to the neurons and, as Outeiro explains, are probably much smaller, invisible to the pathologist. He describes how this might work in simple terms:
“Imagine that you have a lot of trash spread out in a room, it creates a lot more clutter than if you just put the trash all together in one corner. Even if the pile gets bigger, it doesn’t create as much disruption as leaving it around the room.” Presumably, where neurodegenerative disease develops is when this defense system becomes overloaded.
I ask Tiago where he thinks understanding neurodegenerative disease in this way will take us in terms of new discoveries in treatment and prevention.
“Understanding the molecular mechanisms behind every facet — protein misfolding, aggregation, how the cells clear up these protein aggregates, which pathways are involved — will, hopefully, identify new targets we can use for therapeutic intervention. The hope is that we can develop small molecules and inhibitors (if the targets are enzymatically active) that modulate relevant cellular pathways to help them clear the toxic species more effectively and, ultimately, benefit patients.”
Data from the Tiago Outeiro lab
A potential caveat presents itself here: if you target and modulate the “trash collecting” mechanism, could this interfere with the body’s natural defense systems against toxic proteins in an undesirable way?
“At the moment this is also a big question; if we tweak pathways that normally function as in a certain way to do things differently, then of course this could create other problems that we do not foresee right now. That is why it’s very important to understand all aspects of the problem, to get to its root ― uncover the very basic molecular mechanism.
To do this, Outeiro’s group has even employed yeast to help them model certain aspects of neurodegenerative diseases.
“The way you normally study these diseases is to use a mouse model ― all agree that this is closer to humans than yeast. Yet yeast still have the advantage of being eukaryotic cells as well; they share a lot of similarities, in terms of their basic functioning, with mammalian cells ― often with human cells in particular. This presents the possibility of doing certain types of studies and genetic screens that cannot be done in other systems.”
“Of course we cannot say we are going to be curing any of these human diseases just by using yeast as a model. But we can certainly explore all the potential of yeast genetics and tools that have been developed over the years to try to understand what is happening at a very basic level, in a very detailed way. We can then test those findings in other, more complex models; if everything still works the way we think, then we’ve made some progress.”
A newer technique being refined in the Outeiro lab might help them make vital progress that much quicker; it enables them to visualize and study protein misfolding and aggregation in the living brain. He explains the reasoning behind developing the technology…
“The limitation in most studies is that we look at still images of the brain, and therefore miss the dynamics of the different disease processes. If we can image the process of protein aggregation in the living brain we will be much closer to understanding how things develop.”
This promising technology certainly sounds hi-tech: “For the [live brain] imaging we use 2-photon microscopy, a technique that uses a laser that does no damage to the brain tissue yet enables us to see protein dynamics in at least the outer layers of the cortex, through what we call a cranial window. This avoids the need to sacrifice animals (small rodents like mice or rats) in order to observe and interfere with protein aggregation.”
So could technology like this ‘clear up’ our understanding of the role of protein aggregation in disease? It is definitely one of Outeiro’s goals. But, I’m curious, could it also be used to detect neurodegenerative disease? Well the answer is sort of yes and no; it could help with earlier detection, but in a more roundabout way than I imagined ― still, improving disease detection is still on Outeiro’s to-do list…
“Indeed, if we can understand all the players involved in a certain neurodegenerative disease we might be able to detect the real culprit of it earlier. A deeper understanding of the molecular mechanisms involved is essential for the development of novel diagnostic test; thus, we hope these studies will bring us closer to this goal as well.”
The German Neuroscience Society National Meeting
The GNS National meeting is held every two years in Goettingen, Germany. (Source: Wikimedia Commons)
I spoke to Professor Outeiro at the last installment of the GNS national meeting, for which he organized and chaired a session entitled “Molecular mechanisms and spreading of alpha-Synuclein pathology in the brain”. He said says of the meeting and the success of his session:
“The GNS meeting is very important for me in particular because I only moved to the University of Goettingen recently. It is a good way for me to get acquainted with my other colleagues in Germany and the research going on in their labs. We’re lucky in Goettingen because of our cental location and the GNS meeting is usually organized here. It attracts more than 2,000 participants, which provides a great opportunity to meet colleagues, learn about their work, and establish future collaborations here in Germany ― So, it’s very good for that!
“A very important and very hot area at the moment is trying to understand how alpha-synuclein spreads in the brain, because this could have a huge implications for our understanding of how Parkinson’s disease progresses. At this point I thought it would make sense to have a symposium, and invite experts in the field, to inform the community here in Germany of what is being done in alpha-synuclein research and the important things yet to investigate therein.
“The session itself went well, we had great science being presented. For instance we had a graduate student presenting her work on the LRRK2 protein, which is a new subject in this area as it is usually regarded as independent of alpha-synuclein research. However, we now understand that there is a strong connection between the two, and finding an alpha-synuclein interaction with LRRK2 is again bringing us back to the question of protein aggregation and how the cells process these two proteins.”
Author: Deborah Grainger
Related antibodies
Anti-alpha synuclein (SNCA) polyclonal antibody (catalog no. 10842-1-AP)
Anti-APP polyclonal antibody (catalog no. 10524-1-AP)
The post Protein Aggregation: Culprit or Custodian in Neurodegeneration? | Interview with Tiago Outeiro appeared first on The Proteintech Blog.