The main unmet clinical need in Parkinson´s disease and other neurodegenerative disorders, is a therapy capable of slowing the progression of the disease. Currently, only symptomatic treatments are available and despite the huge benefit they make to people living with Parkinson’s, the disease relentlessly moves on its path. A strategy that only impacts symptoms, but the actual course of the disorder, is called “a disease-modifying therapy”. As scientists, that is our goal. That is what we all want to achieve as a community and through the collective decades of work of hundreds of researchers. I am no different in this regard. I started working on Parkinson´s disease as a basic scientist at the very beginning of my career and have never left the field since. The goal has not changed either.

It is a well-accepted opinion that, in order to design a disease-modifying therapy, we need to know what happens at the onset and during the disease and understand what it is that we need to modify. We call that etiology, which means the study of the causes of a given phenomenon (Parkinson´s, in our case). The challenge we face is that we do not know cause(s) of Parkinson´s disease, specifically what molecular and cellular mechanisms underlie its onset and progression. Thus, we need to find those first and then target them to evaluate if this can modify the course of the disease.

Genetics have tremendously advanced our molecular understanding, as for those rarer cases we know the etiology, i.e. the gene mutation. We use those insights to explore cellular pathways that might also be involved in idiopathic Parkinson´s disease and test several experimental strategies, based on said etiology. I developed my personal scientific interest in this research strategy during my post-doctoral fellowship in Vancouver, Canada under the mentorship of Prof. Matthew Farrer, a leading geneticist of Parkinson´s disease, whose guidance greatly helped me shape my personal scientific view. It was during my time of working with Professor Farrer that I was introduced to the WPC as he was involved in the congress organization and reported back to the lab the unique atmosphere of the congress. I made an objective to attend and, upon my move back to Italy, I participated to the 4th WPC in Portland in 2016. The experience did not fail the expectations and I set myself a new aim, participating to the following WPC with attractive experimental results to be more involved in the program.

During the following years, I developed my own line of research in my new institution (Eurac Research) trying to apply the etiology-based approach. We first concentrated on the cell biology of LRRK2 and investigated how the G2019S mutation affects lysosome biology and alpha-synuclein processing in cells. We found that G2019S LRRK2-expressing cells develop higher levels of phosphorylated alpha-synuclein, together with abnormalities in lysosome function, and these defects where reduced by LRRK2 kinase inhibition. This was consistent with previous evidence in the literature and reassured us we were looking at the right things. However, that was not adding pieces to the Parkinson´s puzzle. We needed novel insights into molecular mechanisms. For that, we turned to genomics, the massive studies in which variants in genetic loci are associated to a differential risk of developing Parkinson´s disease in the general population. These offers basic scientists further insights on cellular mechanisms to focus on. We became especially interested in an understudied gene, Rit2, which we knew very little about but triggered our interest for the following reasons:

- It codes for a small GTPase, critical regulators of cellular processes including the trafficking of vesicles;
- The protein is specifically expressed in neurons;
- Its expression is reduced in the substantia nigra of Parkinson’s disease patients.

We wanted to study something new with novel potential and this protein seemed to have exciting premises.

In G2019S-LRRK2 cells, the Rit2 expression was greatly reduced (as in Parkinson´s brains). We engineered the cells to express Rit2 again and observed that all previously mentioned deficits were attenuated, including reduction of phospho-alpha-synuclein, similar to the effects of LRRK2 inhibition. At this point, we thought the two proteins could have something in common and found out that expression of Rit2 was reducing LRRK2 kinase activity. This was a very exciting moment as, up to then, no upstream inhibitor of LRRK2 has been reported. However, we were using cell lines that are very different from neurons and we could have been looking at an epiphenomenon (a sort of artificial event, not really representing reality). We needed to move to neurons and, possibly, to animal models. For this reason, I contacted my good friend Prof. Martin Lévesque at Laval University (Quebec, Canada), a world expert in the biology of dopamine neurons and in vivo manipulations. In his lab, they virally expressed alpha-synuclein in the mouse midbrain to model Parkinson´s disease. At the same time, they specifically expressed Rit2 in the dopamine neurons. The results exceeded our expectations. Rit2 expression strongly attenuated the loss of dopamine neurons in the mouse caused by alpha-synuclein. We were looking at potential neuroprotection. Most of all, we achieved positive results in a model not based on LRRK2 modification, which could widen the application to non-LRRK2 Parkinson’s disease. In this time, we reached 2019 and we all attended WPC in Kyoto (my group and Martin´s group) to present these results. My hope from 2016 became reality as our work was deemed worth not only of poster tour, but also Hot Topic presentation which allowed me to present our date to the full audience in the plenary hall.

After the conference, we were back in the lab to further detail our work, as we still had some missing pieces. We found that Rit2 also reduced accumulation of phospho-alpha synuclein in the mouse brain, reinforcing the validity of the approach. In addition, it prevented the overactivation of endogenous LRRK2 (with no mutations) triggered by alpha-synuclein. This last information is critical for the potential application, as the laboratory of Prof. Timothy Greenamyre recently demonstrated that LRRK2 is overactive in idiopathic Parkinson´s disease as well. Now, we are working to publish our results and submit them to the judgement of the whole scientific community. I also want to acknowledge the WPC for enabling me to get in contact with Prof. Nobutaka Hattori (Juntendo University in Tokyo), member of the organizing committee. We decided to apply to the Invitational Program of the Japan Society for the Promotion of Science (JSPS) and were successful in obtaining funding for me to visit Prof. Hattori´s department for two months in 2020. There, I will collaborate to further our understanding of lysosome biology in Parkinson´s disease and establish a larger network.

The next challenge will be to ascertain if Rit2 could be a valuable target for therapy, as no pharmacologic modulators are available, and we do not know what other effects its activation could produce. We have a lot of work waiting for us and could not be happier with the opportunity to pursue this research. We also hope to have an update on our work to share at the 6th World Parkinson Congress in Barcelona in June 2022.

Mattia Volta, PhD is a Senior Researcher at the Institute for Biomedicine, Eurac Research in Bolzano, Italy. He has attended WPC 2016 and WPC 2019, where he was invited to present his research written above as part of the Hot Topics program. It was due to this presentation that he went on to receive the Stanley Fahn Young Investigator Award, which goes to just one junior investigator at each World Parkinson Congress.

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®