Tau proteins clump together to form neuronal tangles, found in patient brains of more than twenty different neurodegenerative diseases, including various forms of dementia. Last year, researchers at VIB and KU Leuven uncovered that Tau disturbs neuronal communication when it is mislocalized to presynaptic terminals during early disease stages. In a new study, the researchers report that a protein called Synaptogyrin-3 is mediating these effects and could be a new potential target for therapeutic development.
Tau proteins act as scaffolds for the cytoskeleton, providing structural stability for all the cells in our body, including neurons. In many neuronal disease settings, however, Tau gets dissociated and accumulates to form neuronal “tangles”. Such tangles can be found not only in the brains of people with Alzheimer’s disease, but also in many other brain disorders such as Parkinson’s and Huntington’s. How exactly they cause neuronal dysfunction is the subject of intense research.
Tau disturbs neuronal communication early on
Neuronal cells can communicate with each other through the release of vesicles containing chemical messenger molecules. This exchange occurs at the level of the synapse. When Tau gets mislocalized to this area, it locks onto the vesicles, essentially inhibiting signal transmission. In search of ways to intervene in the disease process, prof. Patrik Verstreken (VIB-KU Leuven) and his team set out to understand this interaction better.
Prof. Verstreken: “We knew that if we wanted to somehow prevent the havoc mutant Tau causes at the synapse, we needed to identify its local accomplices. Our experiments all point to Synaptogyrin-3, a protein that is present on synaptic vesicles.”
A new target for intervention
The researchers identified a link between Tau and Synaptogyrin-3, and wanted to verify if it could be exploited to intervene in the disease process. Dr. Joseph McInnes from the team of prof. Verstreken says this was indeed the case: “We found that the interaction between Tau and Synaptogyrin-3 restricted the mobility of the synaptic vesicles, driving the defects in neurotransmission. When we reduced the levels of Synaptogyrin-3 in fly and mouse models, we could prevent the association of Tau with synaptic vesicles, which not only alleviated the vesicle mobility issues but also restored the release of messenger molecules.”
A better understanding of the molecular mechanisms underlying neurodegenerative diseases such as Alzheimer’s and Parkinson’s is sorely needed, as the pharmaceutical industry is reducing its investments in therapeutic development in this area. Prof. Verstreken: “The negative results of many clinical trials underscore that we are trying to develop drugs based on an incomplete understanding of the disease mechanism. This study, identifying Synaptogyrin-3 as a player in Tau pathology, is the perfect example of how exploration of the biological underpinnings of disease can lead to new potential therapeutic targets.”
Questions from patients
A breakthrough in research is not the same as a breakthrough in medicine. The realizations of VIB researchers can form the basis of new therapies, but the development path still takes years. This can raise a lot of questions. That is why we ask you to please refer questions in your report or article to the email address that VIB makes available for this purpose: firstname.lastname@example.org. Everyone can submit questions concerning this and other medically-oriented research directly to VIB via this address.