‘A Needle in a Haystack’: How a New Study Could Revolutionize Parkinson’s Treatment
A year into what was supposed to be a short-term study of a gene linked to Parkinson’s disease, Wu Kaimin was ready to give up. After 12 months of 15-hour days and facing a major deadline to justify her work to her Ph.D. advisor, she still had no idea what role the gene she’d chosen as her research topic, FAM171A2, played in the disease’s expression.
Four grueling years later, she’s glad she stuck it out. Wu’s study, published Feb. 21 in the prestigious journal Science, identified a potential therapeutic target and potential drug candidate for treating Parkinson’s — what Chinese media is calling a “zero-to-one” breakthrough that could significantly accelerate the timeline for finding a cure.
Wu, who received her Ph.D. from Fudan University in 2023, conducted the study together with researchers from the Fudan-affiliated Huashan Hospital, the school’s Institute for Translational Brain Science, and the Shanghai Institute of Organic Chemistry.
According to data from the World Health Organization, there were 8.5 million people living with Parkinson’s in 2019. That number is expected to rise to 13 million by 2040, with China accounting for nearly half the global total.
A neurodegenerative disorder most commonly seen in individuals over the age of 60, Parkinson’s is a progressive, long-term condition with no known cure. Initially manifesting as minor symptoms, such as a diminished sense of smell, constipation, or sleep disturbances, patients gradually develop motor impairments, tremors, and muscle rigidity.
The progression of symptoms can span up to 20 years and is irreversible, Wang Jian, director of the Neurology Department at Huashan Hospital and an advisor on the study, told Chinese media. Current treatments primarily focus on alleviating symptoms. There are no therapies proven to slow the disease’s progression.
Part of the problem has been the difficulty researchers face in identifying viable therapeutic targets — molecules, pathways, or physiological responses that, if changed, can alter or slow the disease’s progression through the body.
That’s what makes Wu’s findings so exciting, Wang says: “The results of this study enhance our understanding of the core pathological mechanism of Parkinson’s.”
“If subsequent translational research and clinical trials progress smoothly, this breakthrough could bring new hope to a battle that has seen repeated failures,” he added.
Earlier this month, Sixth Tone spoke to Wu about the five years she spent “looking for a needle in a haystack,” why her discovery is meaningful, and what her team hopes to achieve next. The interview has been edited for length and clarity.
Sixth Tone: Why is finding a therapeutic target so significant?
Wu Kaimin: One of the core pathological features of Parkinson’s is the misfolding of the key pathogenic protein, alpha-synuclein (alpha-Syn). This misfolded alpha-synuclein can spread from one cell to another, impairing cellular function and ultimately leading to cell death.
Despite numerous attempts, no definitive way has been found to effectively halt the spread of pathological alpha-Syn. A major obstacle has been the lack of a clearly identified therapeutic target.
Previous studies have identified potential targets, but they were mainly found in non-nerve cells, such as microglia. Our discovery, however, focuses on a membrane protein located on the surface of neurons. Given that the prevailing theory suggests alpha-synuclein primarily spreads between neurons, our target holds significant potential for therapeutic interventions.
Sixth Tone: What inspired you to start this research?
Wu: In 2020, our research team identified a variant in the FAM171A2 gene associated with neurodegenerative diseases.
FAM171A2 was an entirely unstudied gene at the time. It is present only in the central nervous system. Given its strong association with neurodegenerative disease risk, we became curious about its role and any potential connection with Parkinson’s, which led us to pursue this line of research.
Initially, we had no idea that the research would take five years. The goal was simply to explore the gene’s function. Not all research yields promising results. However, as we continued investigating, the project gradually evolved, ultimately leading us to our key findings.
Sixth Tone: Why is research on Parkinson’s so challenging?
Wu: Basic research, especially when dealing with completely uncharted genes, is filled with obstacles and uncertainties.
The human body contains over 20,000 protein-coding genes, and the brain alone houses more than 100 billion neurons, which interact in an incredibly complex manner. Each region of the brain has its own unique characteristics, making research even more difficult.
At the outset, we believed that FAM171A2 was associated with Parkinson’s, but we had no idea how. Understanding this connection required extensive exploration, and this process alone took over a year.
Neuroscience research can feel like searching for a needle in a haystack. While we know that alpha-synuclein plays a detrimental role in Parkinson’s, determining how to block its pathological effects remains a formidable challenge.
Sixth Tone: How is FAM171A2 associated with Parkinson’s, and how might your discovery help block pathological alpha-synuclein spread?
Wu: FAM171A2 functions like a “gatekeeper,” selectively recognizing pathological alpha-synuclein and facilitating its uptake into cells. Our goal was to block this “gate” to prevent pathological alpha-synuclein from spreading.
From a library of 7,173 chemical compounds, we identified a small-molecule drug, Bemcentinib, which prevents pathological alpha-synuclein from interacting with FAM171A2, thereby inhibiting its uptake into neurons and potentially slowing disease progression.
Sixth Tone: What were the biggest challenges you faced during your research?
Wu: There were many moments when the research felt like it was at a standstill.
In the first year, the greatest frustration was the lack of direction. After months of effort, we realized that our approach had been completely unproductive, which was particularly stressful given the pressure to complete my Ph.D. By the end of the first year, I had to present my dissertation research proposal, yet I had little to show.
During the third year, our cell experiments were progressing well, but the molecular experiments remained stagnant. At one point, I felt I had reached my limit and might not be able to take the research any further.
By the fourth year, fatigue set in — not just physically but also mentally. After years of work, I was exhausted and also felt anxious about job hunting. The process of writing and revising the manuscript was grueling. Each draft underwent multiple rounds of review.
The manuscript submission process was equally challenging. Our initial submission was rejected outright, and the reviewers provided over 50 comments, each requiring a detailed response and, in many cases, further experimental validation.
As our results gradually improved and gained clarity, I became more confident and learned to approach setbacks with a more balanced perspective. Eventually, the research became more structured and progressed more smoothly.
Sixth Tone: What was your daily life like over the past five years?
Wu: It was incredibly demanding. I typically arrived at the lab around 8 or 9 a.m. and worked until 11 or 12 at night, sometimes even later. Weekends didn’t exist. Each day presented new challenges and countless details that required solving.
Sixth Tone: Do you have a timeline for developing a target drug based on your research?
Wu: It’s difficult to predict. Drug development is an extremely demanding process. One of our current challenges is that the new drug candidates we’ve identified have certain limitations. For instance, their ability to cross the blood-brain barrier is relatively low, but FAM172A2 is primarily distributed in the brain.
Another major concern is determining whether these drugs are safe for human use. This involves understanding the physiological function of the FAM171A2 protein in a healthy body — every protein has a function, and we have yet to fully uncover what role this one plays. Without this knowledge, we cannot predict potential side effects.
We also need to determine the protein structure of FAM171A2 to pinpoint its exact binding site with pathological alpha-synuclein and gain a deeper understanding of their interaction. Only after addressing these issues can we design more effective drugs while ensuring they do not interfere with normal bodily functions.
Once these fundamental problems are resolved, we will move on to animal testing and then human trials.
Each of these steps is time-consuming and carries a high risk of failure, which makes it difficult to predict exactly how many years it will take. Drug development is a long and uncertain journey.
For now, our focus is on understanding the physiological function of FAM171A2 and analyzing its protein structure.
Sixth Tone: Could your findings contribute to research on other neurodegenerative diseases, such as Alzheimer’s?
Wu: Yes. While alpha-synuclein aggregates may have different modifications or structures in each condition, the fundamental mechanism remains similar.
FAM171A2 is a genetic risk factor not only for Parkinson’s but also for Alzheimer’s disease and frontotemporal dementia. But whether it contributes to these diseases through similar pathways or distinct mechanisms is something we are still actively investigating.
Sixth Tone: How do you feel about the excitement surrounding your research?
Wu: Honestly, I feel quite anxious. There are still many unresolved questions, particularly regarding the physiological function of FAM171A2, its structure, and whether it can truly serve as a viable drug target. There is still a long way to go before we can confidently say that a useful treatment will emerge from this research.
Right now, I don’t feel that we’ve reached a point where we can take pride in our achievements. There is still a great deal of uncertainty, and many challenges remain. It will take persistent effort to gradually uncover the answers.
(Header image: Visuals from Jorg Greuel/Getty Creative/VCG and Wu Kaimin, reedited by Sixth Tone)
