Parkinson Canada had the pleasure of attending two important research conferences in September, both to learn more about the current and cutting-edge research behind Parkinson’s disease (PD), and to ensure Canadian representation as a part of the larger, international coalition of movement disorder specialists. First, the Grand Challenges in Parkinson’s conference hosted by the in Grand Rapids, . This is a symposium focused on highlighting the latest updates in Parkinson’s research, with a concurrent meeting for researchers to speak directly with members of the community and better involve them in science
Following this meeting was the International Congress of Parkinson’s Disease and Movement Disorders hosted by the in Philadelphia, which is a platform to bring together researchers internationally to share knowledge and present on advancements made within the larger movement disorders field both clinically and scientifically.
Both meetings welcomed leading researchers, trainees, clinicians, industry representatives, and patient/community representatives from around the world.
A wide range of topics were being presented at both meetings, from the genetics of PD and other movement disorders, disease modifying therapies, clinical trials, better understanding of the biology of neurodegenerative disorders, co-morbid health conditions including mood disorders and gastrointestinal issues, and more. Many of the talks were being delivered from a research perspective for other researchers, but there’s a lot of information that is important to know for the broader PD community. Several key research themes and cutting-edge projects emerged from the conferences:
Important updates on the genetics of Parkinson’s disease
There has been a lot of movement in recent years on improving our understanding of how genes play a role in the development of PD. One of the most important genes that has been uncovered recently is GBA1.
More about GBA1:
GBA1 is a gene that encodes the enzyme glucocerebrosidase, or GCase. This enzyme plays a key role in brain cell function, and mutations/disorders are thought to be linked to alpha-synuclein accumulation in brain cells, causing the characteristic cell death and dysfunction in dopamine-producing neurons that occurs in PD.
Other key genes related to PD include LRKK2, SNCA, PINK1, and more. While we have a strong understanding of these genes and how mutations in them increase PD risk, it’s important to note that studies have historically been done in people of European ancestry and may not be as applicable to people from other ethnic backgrounds. We learned about a new study done in a population with African ancestry that revealed a completely new variant in GBA1 that is not seen in European populations, yet is extremely common in West African populations, and is also strongly linked with the development of PD.
This has some important implications for genetic testing and gene therapies for PD. It’s becoming clearer how there are a wide variety of different mutations that can happen within these PD-associated genes that will affect an individual person’s risk in significantly different ways, and that as genetic testing for PD and gene therapy to attempt to slow or prevent PD becomes more widely researched and adopted, it will require nuance with understanding how a person may be impacted based on a wider variety of individual factors than simply if someone does or does not have a particular genetic risk factor.
We also learned about work being done on how genetic differences can influence treatment outcomes. For example, there’s some evidence that deep brain stimulation (DBS) can affect patients differently depending on which gene is most strongly implicated in their PD diagnosis. Many patients with GBA1-PD experience faster cognitive decline than others, and so their window of opportunity during which DBS is effective may be smaller, while patients with LRRK2-PD potentially have a much wider timeframe during which DBS could be effective due to their generally better prognosis and slower symptom progression.
Promising research on new treatments
While the ultimate end goal is to one day find a cure for PD, we heard a great deal about work being done on treatments that can slow the progression of PD, improve symptoms, and interrupt the pathological processes taking place in the brain. Such interventions are called disease modifying therapies.
Dr. Lorraine Kalia – a Parkinson Canada-funded researcher and movement disorders specialist based in Toronto – is working on a therapeutic that can restore function to the endolysosomal pathway and interrupt alpha-synuclein-related neurodegeneration. This theme, targeting alpha-synuclein either directly or via associated biological processes, is something quite a few researchers spoke about. There are a variety of other studies that are being done examining therapeutic targets that can improve neuroprotection, reduce alpha-synuclein levels in the brain via gene and stem cell therapy, and develop antibodies and immunotherapies that target alpha-synuclein specifically.
More about lysosomes and alpha-synuclein:
Lysosomes play a role in helping “clean” cells and cell parts. If the endolysosomal pathway is not functioning properly, harmful substances that would otherwise be cleared from the brain can build up over time. Overaccumulation of the alpha-synuclein protein in particular is a major contributor to neurodegeneration associated with many diseases, PD included.
While there are many promising therapeutics in the early stages of development, such as those targeting alpha-synuclein, providing direct stimulation of specific brain regions, and more, it’s important to bear in mind that it can be very difficult to bring many therapeutics ultimately to market and/or common practice. To try and speed up this process and improve success rates, many researchers are looking into repurposing or reapplying existing drugs for PD. If a drug has already been approved for use, it comes with several benefits. We will already have data on its safety and efficacy, a large population of individuals who can participate in research, and we will already have knowledge of how those drugs could impact similar biological processes which would act as justification for looking into them as a potential PD treatment.
Ultimately, research on PD treatments is cumulative, in that the more these projects are funded and supported and built upon, the closer we get to helping the largest number of people with PD. That’s one of the best things about conferences like these. By convening experts who are working to solve these problems around the world, it builds a deeply collaborative environment where disease modifying therapies and best practices for treatment are being shared and adopted universally and are having the most impact on patients’ lives.
Combining treatment approaches to address symptom variance
While motor symptoms might often be what one thinks of first when it comes to PD, non-motor symptoms are just as prevalent and may be more disruptive to someone’s daily functioning. Due to the wide variety in how an individual’s motor and non-motor symptoms can present, PD care may require a multidisciplinary team made up of movement disorder specialists and neurologists, physical therapists, mental health professionals and many others.
We heard from one researcher working on a combined physiotherapy and cognitive behavioral therapy approach for movement disorders, and preliminary evidence showed that integrating these treatments improved symptoms and patient quality of life. Mand non-motor symptoms can often be directly interrelated. Pain and motor symptoms, for example, can negatively impact mental health. Thus, addressing physical symptoms can potentially have downstream effects on nonphysical symptoms, and research on this relationship can have implications for more comprehensive patient care.
In much the same way, different brain regions affect both motor and non-motor symptoms in different ways. Dopaminergic neurons are implicated in both symptom types, and performing DBS in brain regions such as the subthalamic nucleus, globus pallidus interna, and substantia nigra has been well-researched and can improve motor symptoms. To improve a wider range of symptoms, researchers are also investigating how DBS in different brain regions or different combinations of brain regions can potentially yield greater impact.
The substantia nigra is a part of the brain that plays a significant role in movement and the production of dopamine. It’s been identified as a potential target for DBS and other direct-brain treatments due to the role it plays in this process, and its connections with other parts of the brain. It’s called the substantia nigra due to neuromelanin, which is a dark, protective substance naturally produced by dopaminergic neurons that colors the substantia nigra as it accumulates. In PD, one of the many pathological processes associated with the disease is the death of dopaminergic neurons in the substantia nigra and a reduction in neuromelanin as the neurons die.
We learned more about research being done into “connectomics,” or how different brain regions and connections between those regions are impacted during movement disorders and how DBS can address this. For example, being able to identify brain circuitry in the prefrontal cortex that’s implicated in tremors specifically. Being able to better map out the complex connections in the brain that are impacted by PD could enable more targeted DBS and address symptoms more comprehensively.
The importance of engaging the community in research
At Parkinson Canada, we strongly value the input of the community in the research process. In addition to being participants in research, people with lived experience and caregivers also serve as research partners who can contribute to prioritization of research topics and shape studies such as their outcomes will have the most impact on people who are affected by the disease. This year we hosted a number of patient engagement in research workshops where researchers and people affected by Parkinson’s came together to have conversations on how research is performed, the role that the community can play in throughout the research process, and how researchers and community members can collaborate to improve outcomes.
Patient engagement was also a key focal point at the Grand Challenges in Parkinson’s conference. One half of the conference, dubbed Rallying to the Challenge, was dedicated entirely to the PD community. During these sessions, researchers would give plain language talks about their work and larger issues within the field to members of the PD community who were in attendance, and then would field questions from the community for the purposes of patient education.
Rallying to the Challenge talks included discussions on the importance of lumbar punctures for collecting cerebrospinal fluid for research and how we can reduce barriers and discomfort that prevent patients from participating in the procedure, pulling back the curtain on how clinical trials work, and why biological sampling and brain donation is important for better understanding PD.
We also attended a session by Dr. Edward Fon, Scientific Director of the Montreal Neurological Institute and Co-Director of the about his work on using stem cells to synthesize neurons for the purposes of testing interventions, identifying potential cell targets for treatment development, and overall, better understanding of the genetics and biology behind PD. We spoke with Dr. Fon after the conference on the importance of community engagement in research, and to provide a bit more information about what he spoke about during his Rallying talk.
An interview with Dr. Edward Fon, Scientific Director of the Montreal Neurological Institute
- You recently attended the Grand Challenges in Parkinson’s Disease meeting in Grand Rapids, Michigan. What were your overall impressions of the conference, and their focus on not just presenting research to other researchers, but engaging patients with the Rallying to the Challenge sessions?
- It was a great conference and brought together some great talks and speakers. It was structured very well with the theming (therapeutics, cell models, imaging modalities, all very topical and addressed issues at the forefront of new discoveries in PD and working toward new treatment options). Rallying to the Challenge was very stimulating as a researcher and clinician to speak with patients and be able to present new developments happening at the Neuro to a group that would directly benefit from our work and have their lives improved. We should be doing more of that in the field. It is a special skill to try and “translate” your work to nonspecialists and really forces you to take a step back and clarify things not just for them but for yourself and help shine a light on the importance of the work. Patients ask really insightful questions that you might not have otherwise thought of about things scientists may have otherwise taken for granted, and that question of “why” comes more from them than from professional audiences in my experience.
- What are your thoughts on the importance of researchers from Canada attending these international conferences, and ensuring that work is being represented on a global scale?
- Canada has often punched above its weight in neuroscience and PD specifically and has played a role in some really key discoveries around the link between PD and pesticides, genetics, and L-DOPA. We need to be present at these meetings because Canada doesn’t often get as much recognition as it really needs or deserves based on the importance of work coming out of our institutes. It’s also important for patients because the funding for research in Canada is well below what it is in the US, and we often get much more bang for our buck given those financial limitations, but we also need to try and advocate for more money coming in to fund research. There are many things we do as a field better than in the US in my opinion, but research funding through the NIH is something they do get right, and we can learn from their example. Our market is also smaller and not quite as lucrative for pharma, so new drug trials often don’t take place here, and Canadian patients don’t get access to important treatments until much later down the line. Reps from relevant industries attend these conferences, and that gives us an opportunity to improve Canada’s presence.
- You spoke a bit about the importance of ensuring a more equitable distribution of research on understudied genes in both your Rallying session and your plenary session. Could you please expand on that a bit, and discuss where you see the field going in the future with regards to exploring new avenues for therapeutic targets and disease etiology?
- Scientists follow fads just as much as anyone else in society, and people naturally get drawn toward things that are in fashion. 40 years ago, we didn’t know any genes that were involved in PD, now we know upwards of 80, but still only 8-10 are the ones getting all of the attention. Scientifically, we still don’t fully understand all of the genetics of PD, and so identifying understudied genes that have a high likelihood of being relevant is extremely important. It also has implications in drug targets, proteins, enzymes, etc., to improve coverage of how we’re able to treat PD. It’s a complex disease where some patients respond to some targets, others don’t, so it’s really not a one size fits all approach. It’s easier to hop on the bandwagon and look at things that are established and can be studied through existing technology, but you kind of have to start from scratch sometimes. There’s potentially more risk with starting from scratch, but potentially so much reward. Fortunately, with CRISPR and gene editing, it’s so much easier than it used to be in the past.
- Do you have any other thoughts on important research that was presented, or takeaways that you think would be good for people with lived experience to know about?
- I was particularly struck by a talk from Cornelis Blauwendraat on genetics, and his approach to examining genes in populations other than the typically studied white European ancestries. They identified a variant specifically in African ancestries in GBA that plays an extremely important role in the structure of RNA that can drastically impact the development of PD. I was naturally drawn more toward talks on single-cell approaches identifying vulnerable subpopulations of dopamine neurons via single-cell RNA sequencing. I’m a cellular scientist by trade, and so that really stood out. At first glance the Cornelis study did a GWAS, and they didn’t find too much aside from GBA and another gene, but they managed to identify that the biology behind it is completely different than the white European ancestry populations.
More about GWAS:
GWAS, or genome-wide association studies, are a type of genetic research that examines large sets of DNA (the genome) of a study population, looking at variations between groups in genes associated with different diseases or risk factors.
Together, these conferences allowed us to have a look into work being done around the world on improving the symptoms of PD patients, understanding how the disease works, and on potential future therapeutics that have implications in halting or preventing the disease. We were very privileged to attend and always leave these conferences feeling very encouraged. We’re looking forward to next year’s meetings and will continue to do our part to amplify work being done within Canada, and to report back to patients and the community on the current and future state of PD research.