Thinking Outside the Box: Beyond the Conventional Effects of Alpha-Synuclein
For more than 100 years (108, to be more precise), we have known that the brains of Parkinson’s disease (PD) patients accumulate protein inclusions (or aggregates), known as Lewy bodies (since they were first described by a German scientist called F. Lewy). For several decades, we only knew these protein inclusions existed, but we did know what they were made of. Since they accumulated, predominantly, in the brains of patients with PD, we thought they were some sort of protein garbage that was causing disease. It was only 23 years ago that scientists identified a major component of these inclusions – a protein known as alpha-synuclein (aSyn). The name of the protein was meant to reflect the fact that it was present in the synapse (the name of the region that connects two neurons in the brain) and in the nucleus of the cells (the compartment where our genetic code is kept and that functions as the “mission control center” of the cell).
Since 1997, we have been intrigued and fascinated about aSyn, and we have come a long way in our understanding of “who” this protein is, and what it does in the cell.
Over the years, the prevalent theory has been that Lewy bodies, made of aggregated aSyn, are the culprits in PD. However, the truth is we still cannot definitively say that it “causes” PD just because it is a major component of Lewy bodies. In fact, several lines of evidence from the PD field, and also from studies in Alzheimer’s disease and in other neurodegenerative diseases, suggest we may need to change the way we think about the protein aggregates, since strategies aimed at clearing them from the brains of patients have, thus far, failed to produce significant improvements in clinical trials with patients. Therefore, we need to think outside the box, and come up with new ideas and hypothesis that we can test in the laboratory.
One of these ideas, which has been underexplored, has to do with the role aSyn plays in the cell. Conventionally, aSyn is primarily studied in the context of the synapse. However, the protein was also observed in the nucleus of cells, but this has been overlooked. We think this needs additional study and, therefore, this has been one of the topics in my laboratory, as we believe this may provide us novel clues about the disease mechanisms and, therefore, about possible therapeutic strategies.
In recent studies in my lab, we confirmed aSyn can occur in the nucleus of neuronal cells, an observation that had been given poor credit for several years. We have now gathered strong evidence that the protein can move into the nucleus and bind DNA, i.e., our genetic code. We found that, by interacting with DNA, aSyn can induce alterations in the expression of important genes, and lead to DNA damage. This damage is something we ought to avoid, as it will interfere with the normal function of the neurons and, therefore, cause problems in the normal function of the brain. We are currently studying the factors that influence the movement of aSyn into the nucleus and we believe that certain chemical alterations in the protein, known as posttranslational modifications, might play a key role in this process.
In other ongoing studies in the laboratory, we are also studying other effects of aSyn in the nucleus that can also lead to changes in normal gene expression. These effects are known as “epigenetic-alterations”, as they influence gene expression without directly affecting the DNA. Among these epigenetic alterations, we are particularly interested in effects on small molecules known as micro-RNAs, since we know these can affect protein expression.
What do we hope to discover?
With these studies, we hope to develop a better understanding of the normal biology/function of aSyn, especially concerning its effects in the nucleus of our cells and, more specifically, on gene expression. We also hope to identify factors that influence the distribution of aSyn in the cell, in order to understand what causes it to go into the nucleus. Ultimately, we hope that our studies, which focus on aspects that are outside the main stream, may lead to the discovery of novel targets for therapeutic intervention and, possibly, also to novel diagnostics. Stay tuned.
Prof. Dr. Tiago Fleming Outiero, PhD, presented at the WPC 2016 and spoke on the WPC Scientific Update 2015 webcast. He is currently Director of the Department of Experimental Neurodegeneration, University Medical Center Goettingen in Goettingen, Germany.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions of the World Parkinson Coalition®