NeuroVoices: Andrew Singleton, PhD, on Expanding the Genomic Pool for Parkinson Disease

Andrew Singleton, PhD

While the actual cause of Parkinson disease (PD) remains a mystery, scientists believe that a combination of genetic and environmental factors could play a major role. Most people with PD have no known genetic link; however, a small population, about 10-15%, have a genetic cause. Previous research has shown that a handful of ethnic groups, like the Ashkenazi Jews and North African Arab Berbers, more commonly carry genes linked to PD. There are several genes known to contribute to PD, including SCNA, PARK2, PARK7, PINK1, and LRRK2.

Genetic regional and racial differences in PD are observed for many genes. For example, the MAPT gene, encoding the microtubule-associated protein tau, was detected as a risk factor for PD in a genome-wide association study (GWAS) of a Caucasian population, but not in a GWAS of a Japanese population. Despite the fact that studies of familial PD have identified approximately 20 different causative genes, several in the field, including Andrew Singleton, PhD, believe there is a need for a more comprehensive understanding of the condition worldwide.

At the 2023 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held August 27-31, in Copenhagen, Denmark, Singleton, a distinguished investigator at the National Institutes of Health, gave the C. David Marsden Lecture, discussing the need to expand the global genetic pool of PD. As part of a new iteration of NeuroVoices, Singleton provided answers on the significance of genetics in the treatment paradigm of PD, the next steps in research, and the overall outlook of gene therapies and potential disease-modifying agents.

NeurologyLive^®: Could you provide some insight into your presentation?

Andrew Singleton, PhD: Absolutely. It was truly an honor for me to deliver the C. David Marsden Award lecture. During the presentation, I focused on the topic of globalizing Parkinson genetics and the remarkable advancements we've achieved over the past three decades. We began with the identification of the first disease-causing mutation in 1997, and since then, there has been a consistent stream of progress. However, it's important to note that much of this progress has been concentrated within populations of Northern European descent. My main point was that if we aim to utilize precision medicine, where treatments are tailored to a patient's specific mechanism of disease, we must develop a comprehensive understanding of the condition worldwide. This requires delving into disease patterns across diverse global populations. I delved into the challenges associated with this issue and proposed a solution – the global Parkinson's genetics program.

We've made substantial discoveries about genetics and PD. What comes next?

Certainly, we have indeed amassed a wealth of genetic knowledge. Nevertheless, there is still a considerable amount left to uncover, especially when it comes to the genetic influences that are not well understood within Northern European ancestry populations, which have been the primary focus of our research thus far. In other ancestral populations, there is a significant lack of information. Despite discussing a major breakthrough from the global Parkinson's genetics program during the lecture, I view this as merely scratching the surface. There is a multitude of work that remains ahead of us.

What do we currently understand about racial and ethnic disparities in the progression of PD?

You've raised an important question. Presently, our understanding of the variations in the presentation and course of Parkinson's disease among different ancestral backgrounds is quite limited. There is a distinct scarcity of data available on this topic, placing us at an early stage of exploration. Addressing this gap is one of the primary goals of the global Parkinson's genetics program – employing genetic insights to decipher the differences and commonalities in disease across diverse ancestral groups.

What are your thoughts on the potential of gene therapy? Is it as feasible as it's often portrayed?

Gene therapy is certainly generating considerable buzz, and we are still in the nascent stages of applying modern gene therapy techniques. In my view, gene therapy is a plausible therapeutic avenue that warrants pursuit. Whether we target genes identified through mutation detection or those associated with risk factors, and whether these genes play a central role in the intricate network of disease processes, these are aspects that are yet to be determined. Nonetheless, gene therapy exhibits promising potential as a therapeutic strategy.

Could you elaborate on the main research priorities that the Parkinson's disease clinical community should prioritize moving forward?

Research in Parkinson's disease spans numerous facets. From my perspective as a geneticist, I emphasize the significance of comprehending the molecular-level mechanisms underlying the disease. Ultimately, achieving effective treatment and prevention hinges on understanding the fundamental disease processes. Equally vital is the exploration of early detection and prediction, which involves endeavors like biomarker research. Ideally, we aspire to reach a point where mechanistically-driven therapies can be tailored to a patient or a group of patients, even before symptoms arise. This necessitates robust disease prediction methods.

Are there more efficient ways to seek out disease-modifying therapies for PD?

My focus primarily centers on the mechanistic understanding of the disease. In the consortium I'm engaged with, the global Parkinson's genetics program, our strategy revolves around extensive collaboration and data democratization. This approach entails ensuring that data is accessible, actionable, and that researchers possess the necessary skills and resources to utilize this data effectively. By convening experts worldwide to tackle specific topics, we accelerate our comprehension of the underlying disease mechanisms.

Is there anything else you'd like to emphasize about your presentation?

I'd like to convey my optimism about the future. Collaborative efforts with research groups globally and a shared commitment to understanding disease across diverse populations are crucial for progress. Our network already involves thousands of researchers, yet we warmly welcome more collaborators. I eagerly anticipate partnering with your audience in this endeavor.

Click here for more coverage of 2023 MDS Congress.

REFERENCE
1. Funayama M, Nishioka K, Li Y, Hattori N. Molecular genetics of Parkinson’s disease: contributions and global trends. Journal of Human Genetics. 2023;68(125-130). doi:10.1038/s10038-022-01058-5