Unraveling the cellular basis of Alzheimer's and Parkinson's Disease
In the “From the lab to…” series, we highlight our team’s scientific expertise by providing the spotlight to colleagues with a background in research. In this edition, Jessica Vargas, PhD, writes about her research background and post-doctoral experience.
Neurodegenerative disorders are therapeutically challenging
The brain is the most complex organ of the human body and the one we understand the least. Still many open questions regarding its function remain unanswered. For instance, we do not know yet how memories are created, stored, and retrieved when necessary. Our lack of understanding of basic molecular and cellular mechanisms driving the function of the brain has greatly impacted the development of therapeutic strategies for treating brain disorders.
Until now, there is no cure for neurodegenerative disorders, such as Alzheimer’s or Parkinson’s disease, and probably many years will pass before the development of an effective treatment for these devastating disorders. To this aim, understanding how the brain works is, therefore, paramount. Neurodegenerative disorders are very variable in terms of symptoms; Alzheimer’s disease is characterized by a progressive loss of memory, while Parkinson’s disease mainly affects the patient’s movements. However, these disorders have common molecular features: they originate by the aggregation of one or more proteins and the progression of the symptoms seems to correlate with the spreading of these aggregated proteins throughout the brain.
Thus, possible therapeutic strategies can be directed towards blocking the aggregation of the protein or preventing the spreading of the aggregates already formed. The problem with the first strategy is that by the time the disease is diagnosed (i.e., when the first symptoms are evident), the protein is already aggregated, and the spreading has started. Then, stopping or slowing down the spreading of the aggregates seems to be best therapeutic approach for these disorders.
Postdoctoral research with groundbreaking discoveries
Despite extensive research on the mechanisms that underlie the spreading of aggregated proteins in the brain, there is still no scientific consensus on how these aggregates transfer from one cell to the other. Understanding the mechanisms by which the aggregates are able to reach new areas in the brain, is crucial for the design of the new therapies that target the spreading of the aggregates.
During Jessica’s first postdoc at the Pasteur Institute in Paris (2014-2018), she studied the mechanisms involved in the intercellular spreading of Tau aggregates (protein involved in Alzheimer’s disease) and α-Synuclein aggregates (protein involved in Parkinson’s disease).
Describing the significance of this work, Jessica says, “The results were groundbreaking, as we discovered that these protein aggregates transfer from cell-to-cell through membranous connections similar to a cellular bridge, named tunneling nanotubes (TNTs). TNTs connect distant cells, allowing the transfer of various cellular materials.”
These cellular structures were described for the first time in 2004 and since then have been found in several cell types but have never been seen in neurons before.
Discovering new therapeutic opportunities for Parkinson’s and Alzheimer’s disease
Describing the impact of their work, Jessica first highlights their earlier publication focusing on the intercellular spreading of α-Synuclein aggregates in Parkinson’s disease: “We showed for the first time that TNTs can be formed between neurons. Using state-of-the-art imaging techniques, we were able to follow the transfer of α-Synuclein protein aggregates through TNTs from neuron-to-neuron. Moreover, in this work we described the cell signaling cascade that controls the formation of TNTs and we identified druggable targets within this cascade that can be used to stop the formation of the nanotubes.”
Following the hypothesis that by stopping the spreading of the aggregates it will be possible to block the progression of the disease, this work opens the door to new therapeutic opportunities for the treatment of Parkinson’s disease.
In their subsequent paper on Alzheimer’s, they discovered that Tau protein aggregates can also transfer from cell-to-cell, predominately using TNTs as mechanism of transfer.
“This work provided a new neuronal cell reporter system to study the transfer of Tau aggregates. This system allows to track in real time the aggregation of Tau protein and to follow the transfer of the aggregates.” Jessica says, “Thus, the system constitutes an innovative tool that can be used for the screening of compounds designed to block the spreading of Tau aggregates and eventually lead to new therapeutic options for Alzheimer’s disease.”
Work with real impact
While reflecting on the significant impact of her research, Jessica highlights the substantial task ahead: “Although our studies provide the groundwork for future therapies for Alzheimer’s and Parkinson’s disease, there are still several open questions that need to be addressed before designing and testing new drugs for these disorders: Are TNTs present in the human brain? If so, do they represent the main way of transfer of aggregated proteins? What happens if we block the formation of TNTs in the brain? Would this also impair the normal brain function?”
Jessica adds, “Still much research is needed to answer these and other open questions in the field, but our results cement the path for new and exciting research aiming to understand brain physiology in health and disease.”
Bringing brilliant innovations to life at Catalyze
After a fruitful career in research focused on finding therapies for incurable diseases, Jessica decided she could make more impact for patients by adapting her expertise to life sciences consultancy. Jessica explains what inspired the transition to Catalyze: “Almost 3 years ago, my father was diagnosed with Parkinson’s disease. This sad news motivated me to take a more active role in helping to bring promising research results to the patients that, like my father, need efficient therapies for their incurable diseases.”
Today, as a life science consultant at Catalyze, Jessica can apply her background to help academics and entrepreneurs take crucial steps towards the development of potentially life-changing, or life-saving treatments.
Jessica says, “As a Consultant at Catalyze I have had the opportunity to be directly involved in projects that aim to make a difference for patients. My strong scientific background has helped me to easily identify and highlight the strengths of new drugs and medical devices developed by several companies that are looking for funding to change the lives of thousands of patients hoping for efficient treatments. Through my work at Catalyze, I aim at facilitating the fast development of novel therapies and innovative solutions to reach the market and change people’s lives.”
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