What are the most exciting projects currently underway in your lab, and what are the “big questions” you are trying to answer?
We have three projects in my lab that I’m particularly excited about.
1. Understanding LRRK2 Activation in Parkinson’s Disease. Our first major project focuses on understanding the molecular mechanisms by which the VPS35 D620N Parkinson’s-associated mutation activates the LRRK2 (Leucine-Rich Repeat Kinase 2) pathway. We believe this mutation induces a physiological stress response, which plays a critical role in the progression of Parkinson’s disease. Our data suggest that this mutation leads to a type of endolysosome dysfunction, which in turn triggers aberrant recruitment of LRRK2 to lysosomes, where it becomes activated. We aim to define the nature of this stress, how it is sensed by the cell, and how it leads to LRRK2 activation. This research could provide critical insights for better diagnosis and therapeutic targeting of LRRK2 driven Parkinson’s disease.
2. Investigating the Role of RILPL1 and TMEM55B in LRRK2-Mediated Pathways. Our second project builds on our discovery that LRRK2 activation and its recruitment to lysosomes leads to the phosphorylation of Rab GTPases, which subsequently interact with a phospho-binding protein called RILPL1. Interestingly, RILPL1 then engages with TMEM55B, a transmembrane lysosomal membrane protein that our preliminary data suggest may function as a novel E3 ubiquitin ligase. We are currently investigating the enzymatic activity of TMEM55B, its regulation by LRRK2, and trying to uncover its downstream targets. Understanding this pathway could uncover new regulatory mechanisms of lysosomal function and highlight potential therapeutic targets.
3. The MJFF LITE Initiative, Targeting the LRRK2 Pathway: The third project is a large-scale initiative in collaboration with the Michael J. Fox Foundation (MJFF), called the LITE (LRRK2 Investigative Therapeutics Exchange) Initiative. One of the goal of this program is to identify novel strategies to inhibit LRRK2 activity beyond Type 1 kinase inhibitors that are currently being tested in clinical trails, bringing together researchers from around the world. Currently, we are exploring 17 potential new approaches to suppress the LRRK2 pathway, an ambitious but highly promising effort. I am particularly excited about this project because it has the potential to translate fundamental research into tangible therapeutic interventions for Parkinson’s disease.
Was there any event, person, etc. that inspired you to pursue a career as scientist?
Growing up, I was very close to my grandfather, and when he developed Parkinson’s disease, I saw firsthand how devastating it can be. I remember being particularly interested in the medications he was taking, how they worked, their effects, and, more frustratingly, how limited they were in truly slowing or stopping the disease. This experience made me realize just how crucial medical research is in developing better treatments for conditions that still lack effective therapies. Beyond that personal connection, I was fortunate to have inspiring teachers in chemistry and biology, both in school and later at university, who encouraged my curiosity and passion for science. The first time I worked on a research project, I had a moment of realization—the excitement of discovery, of being the first person to uncover how a biological pathway functions. That feeling was unlike anything else, and it solidified my decision to pursue a career in research.
You have made major contributions to understanding LRRK2 and its role in Parkinson’s disease—how do you see this research evolving in the coming years?
I hope that the work being done in our lab, along with the efforts of many other researchers studying the LRRK2 pathway, will lead to a much deeper understanding of how this pathway works and functions and contributes to Parkinson’s disease. This knowledge could help us develop better tools for early diagnosis, enabling us to identify individuals with LRRK2-driven Parkinson’s disease more accurately and at an earlier stage. Ultimately, I hope this research will provide key insights and technologies that allow scientists to design safer and more effective therapeutic strategies that can halt or slow disease progression rather than just managing symptoms. In the long term, I envision a future where it may be possible to diagnose LRRK2-driven Parkinson’s disease before symptoms even appear, allowing for early intervention that could prevent or significantly delay the onset of the disease’s hallmark symptoms.
Your research has led to insights with potential therapeutic applications. How do you view the intersection between basic science and translational research?
Louis Pasteur once said, “There is science and the application of science, bound together as the fruit of the tree which bears it.” I firmly believe that translational research cannot exist without a strong foundation in fundamental science. Groundbreaking therapies arise from deep biological insights, and without basic research, we would lack the knowledge needed to develop innovative treatments. It is crucial that funding systems and research institutions support both basic and translational research equally and ensure that these areas remain well-connected. By fostering a seamless integration between discovery-driven science and applied research, we can accelerate the development of new, effective therapies that have the potential to transform patient care.
Mentorship is a key part of your career. What do you think makes a great mentor, and what have been some of the most valuable lessons you’ve learned from your own mentors?
Training and mentoring the next generation of scientists is one of the most important aspects of my work. In many ways, I feel that my greatest contribution to research is not just the discoveries we make, but the scientists I help train and support—who then go on to make significant contributions of their own. Everyone has a different mentoring style, and there’s no single “right” way to do it. My approach is to dedicate substantial time and effort to trying to understand what my mentees are working on and what their ambitions are. I actively engage in discussions about their research, helping them refine their ideas and formulate concrete plans to achieve their goals. This involves reading their papers, providing critical feedback on grant applications, and sometimes even connecting them with experts in areas where I may not have as much expertise. A key part of mentoring is also helping trainees navigate challenges, whether it’s a rejected paper, an unsuccessful grant application, or setbacks in the lab. Science is full of obstacles, and I believe that learning how to handle failure and persist through difficulties is just as important as celebrating successes.
One piece of advice that has stuck with me comes from my PhD supervisor, David Trentham, who once told me: “Dario, it’s important that you develop a quantitative assay for everything you work on, once you have an assay, you can do anything.” This principle has shaped my approach to research, and even today, I still prioritize developing robust assays and tools to better understand and study the biology we work on, and this is one of the aspects of my research that I enjoy the most. My postdoctoral supervisor Philip Cohen once told me that there is a very fine line between success and failure. They emphasized that conducting an experiment carefully, with the right controls and attention to detail, takes no more time than doing it poorly, but makes all the difference in the outcome.
Was there a defining moment or person that inspired you to pursue a career in science? Did you ever consider a different career path?
My greatest influences have been my PhD supervisors, Ian Trayer and David Trentham, and my postdoctoral supervisor, Philip Cohen. Each of them had distinct personalities and scientific approaches, but all motivated me in different ways to pursue a career in research. I vividly recall that after my first year of PhD research, I had little to no data, and I lost confidence in my ability to succeed in science. I became so discouraged that I applied for a position at a leading accountancy firm, and to my surprise, they offered me the job. However, before starting, I had to complete a standard aptitude test. I took the test, but apparently, I performed terribly and failed. The company informed me that I was not suited for accountancy and should stick with science. Looking back, that aptitude test may have been one of the best things that ever happened to me. Without it, I might have left my PhD and taken an entirely different career path. Instead, I stayed in science, pushed through the challenges, and ultimately built a career that I am deeply passionate about.
Science is full of challenges and setbacks. Can you share a moment in your career when things didn’t go as planned and how you navigated it?
During my postdoctoral research, I spent four years trying to understand how RAF protein kinases are activated. This project turned out to be far more complex than I had initially anticipated, and despite an enormous amount of work, I was unable to fully unravel the regulatory mechanisms of this enzyme. As a result, I did not publish any papers from this long period of research. Although this was a significant setback, devoting years of effort without a tangible outcome—I chose to view it as a critical learning experience. It forced me to analyze what went wrong, refine my approach, and develop greater resilience. The lessons I took from this project have made me a better scientist, teaching me that in research, setbacks are inevitable, but the ability to adapt, persist, and keep pushing forward is crucial. This experience also reinforced an important truth: science does not always lead to immediate success, but every challenge presents an opportunity to grow and improve.
Beyond the lab, what are some of your hobbies or interests? How do they complement or contrast with your work in science?
As scientists, we work incredibly hard, probably too hard, and there’s always more to do. However, I believe it is crucially important to take time away from the lab, to spend with family and friends, travel, relax-doing nothing or watching TV or read a book, listen to a podcast and engage with people outside of our immediate scientific circle. Often, stepping away from work provides fresh perspectives, and some of the best ideas come when you’re out for a walk, going for a jog, or even chatting with a neighbour or a stranger during your travels. It’s also essential to prioritize self-care and mental well-being. Someone once told me, “Work hard, play hard,” and I think that’s good advice. Balancing dedication to research with time for relaxation and reflection is key to sustaining creativity, motivation, and long-term success in science. This is easier said than done!
What advice would you give to PhD students and postdocs who are just starting their careers in biomedical research?
This is one of the best times of your life, you have the freedom to immerse yourself in science while your mentors worry about securing research funding. Enjoy the process, because research is more than just a job, it’s a vocation. Follow your curiosity, let it guide your experiments, and embrace the excitement of discovery. My advice is to dive deep into hands-on research. Avoid overthinking or setting unrealistic expectations, focus on the research itself, and success will follow. Also, be open to opportunities, seize them, even the small ones. Sometimes, seemingly minor chances can open doors to an entirely new world of possibilities and achievements.