Life Sciences Breakthrough Prize Laureate Thomas Gasser: If it's all Parkinson's disease, why do we need different treatments?

Today, I would like to discuss some recent discoveries in genetics.Parkinson's Disease Treatmenta new paradigm, as well as potential directions for future development.

About two hundred years ago, in 1817, James Parkinson first described the disease that would later be named after him. He observed six patients at the time and recordedResting tremor..., posture, and gait changes, among other major clinical manifestations. Of course, at that time, people did not yet know that Parkinson's disease would later become an increasingly heavy health burden.

We are now very familiar with the state of Parkinson's disease after progression: patients may exhibit shuffling gait, resting tremors, and limb rigidity, while standing posture and gait become unstable, and postural reflexes are also impaired. These clinical symptoms are largely associated with the extensive loss of dopaminergic neurons.

Fortunately, many effective treatments are now available to alleviate these symptoms. For instance, in a single patient, deep brain stimulation can lead to a marked improvement in walking ability and greater bodily stability within just a few minutes. This demonstrates that the symptoms of Parkinson's disease are treatable.

However, the problem is that an improvement in symptoms does not mean the disease itself has stopped progressing.

Before Parkinson's disease is truly diagnosed, there is often a long prodromal phase. Patients may first experience a reduced sense of smell or develop conditions such as REM sleep behavior disorder. In other words, the disease may have already begun to progress well before the motor symptoms we are familiar with today actually appear.

This also raises a very important question: if we can diagnose Parkinson's disease earlier, before typical clinical symptoms appear, we may have more opportunities for truly effective interventions. By the time clinical symptoms become clearly evident, the patient's nervous system may already have suffered severe damage. As the disease progresses, both motor and non-motor symptoms will continue to worsen.

Genetics has changed.

How We Understand Parkinson's Disease

In the late 1990s, researchers discovered the first gene mutation capable of causing familial Parkinson's disease. This discovery has offered a completely new perspective on our understanding of Parkinson's disease.

In a family from southern Italy, researchers discovered that some patients carried the same genetic mutation and exhibited highly typical Parkinson's disease. The condition follows an autosomal dominant inheritance pattern. Subsequently, it was recognized that this is associated with α-synuclein.

It has long been known that the aggregation of Lewy bodies is a critical pathological hallmark of Parkinson's disease. Further genetic studies have revealed that not only point mutations, but also gene dosage alterations such as duplication or triplication of the SNCA gene, can lead to increased levels and aggregation of α-synuclein, ultimately causing Parkinson's disease.

Of course, such mutations are extremely rare and can explain only a small fraction of Parkinson's disease cases.

This also means that many other genes can cause Parkinson's disease. Different genes may lead to either autosomal dominant or recessive inheritance; some patients develop symptoms at an early age, while others do so later; and in some individuals, cognitive impairment and dementia are more prominent.

When we examine these genes together, we find that they point to several distinct biological pathways.

One pathway is associated with protein aggregation, specifically the alpha-synuclein mentioned earlier; certain genes influence the clearance of protein aggregates, while others affect vesicle sorting and transport as well as lysosomal function, such asGBA1Other recessive genes also affect mitochondrial function.

Although these pathways are not entirely identical, they may ultimately converge on the same outcome—the loss of dopaminergic neurons.

Therefore, next I would like to focus on three pathways closely related to disease-modifying therapies: alpha-synuclein.LRRK2and GBA1.

Alpha-synuclein:

Can we prevent the continuous aggregation of abnormal proteins?

First is alpha-synuclein. Today, many disease-modifying therapies are attempting to target this protein.

Misfolding of alpha-synuclein is a very common process in Parkinson's disease. The triggers for this process can vary; they may include point mutations, gene duplication, or triplication as recently discussed, or they may be influenced by environmental factors such as head trauma and exposure to certain toxic substances, including pesticides.

Ultimately, these factors may promote the aggregation of alpha-synuclein into Lewy bodies, accompanied by dopamine deficiency, leading to the clinical manifestations of Parkinson's disease.

A particularly interesting development is that we have begun attempting to track this protein aggregation process in living patients.

One approach is the seed amplification assay. We obtain a small volume of cerebrospinal fluid via lumbar puncture, which may contain pre-formed alpha-synuclein "seeds." Under controlled experimental conditions, continuous shaking induces these seeds to trigger the aggregation of additional monomeric proteins, while fluorescence signals are used to monitor the entire process.

In other words, we are developing a method to determine whether abnormal aggregation of alpha-synuclein has already occurred within a living patient.

This is crucial for disease-modifying therapies, as detecting the pathological process enables us to determine whether the treatment truly targets the disease itself.

One approach involves using antibodies to prevent the continued spread of abnormal alpha-synuclein between cells. A series of related studies and clinical trials have already been conducted.

Unfortunately, based on some current clinical studies, the treatment group has not yet reached the pre-specified primary endpoint compared to the placebo group. However, in follow-up assessments, we observed some positive trends: the disease progression curve suggests a potential slowing of progression.

Therefore, this path has not been halted. The relevant Phase III studies are still ongoing. The core hypothesis remains that if abnormal aggregation of alpha-synuclein can be reduced, it may be possible to slow disease progression.

LRRK2: It's also Parkinson's disease.

However, the underlying pathology may not be the same.

The second pathway is LRRK2.

We identified LRRK2-associated variants in our familial Parkinson's disease studies around 2004. This represents a highly typical form of familial, autosomal dominant inheritance.

However, a crucial insight brought to us by LRRK2 is that even when patients appear clinically to have typical Parkinson's disease, the underlying pathology may not be identical.

Some patients exhibit classic Lewy bodies and α-synuclein pathology, yet a subset of LRRK2-related cases do not show prominent α-synuclein aggregation. This is critically important, as it reminds us that we cannot assume all Parkinson's disease arises from a single pathological pathway.

LRRK2 is a kinase involved in multiple molecular processes, including the sorting and transport of intracellular proteins and vesicles. Certain LRRK2 mutations lead to kinase hyperactivation; therefore, a logical therapeutic strategy is to use specific kinase inhibitors to suppress this process.

Clinical trials investigating this mechanism are now underway. Although some studies have not yet achieved the desired clinical endpoints, certain biomarker findings provide a rationale for further research, and thus this line of inquiry continues to advance.

This once again underscores that, to pursue disease-modifying therapy for Parkinson's disease, it is first essential to identify which specific biological pathway is truly aberrant in the patient.

GBA1: A faster-progressing

Parkinson's disease subtypes with a higher risk of cognitive impairment

The third very important gene is GBA1.

The enzyme encoded by GBA1 is associated with Gaucher disease. It has long been known that severe deficiency of this enzyme leads to Gaucher disease. Subsequent research has shown that even in individuals without typical Gaucher disease, carrying a GBA1 variant significantly increases the risk of developing Parkinson's disease later in life. Based on our observations at the time, this risk could increase several-fold.

GBA1-related Parkinson's disease is also a subtype of great interest.

When comparing sporadic Parkinson's disease, LRRK2-associated Parkinson's disease, and GBA1-associated Parkinson's disease, it becomes evident that their natural histories are not entirely identical. LRRK2-associated cases can sometimes be relatively mild, whereas GBA1-associated patients often experience more rapid progression, with an earlier age of onset and a more pronounced risk of cognitive impairment and dementia.

This means that, for individuals carrying the GBA1 mutation, this is often not good news. Particularly regarding non-motor symptoms, current treatment options remain quite limited.

Mechanistically, there is a close link between GBA1 dysfunction and α-synuclein. When the activity of the relevant enzyme declines, α-synuclein levels and aggregation may increase, thereby establishing a mutually reinforcing pathological process.

Studies have also shown that patients with GBA1 variants develop cognitive impairment and dementia earlier, and even in relatively milder cases, disease progression is typically faster than in non-GBA1 patients.

Therefore, our team and partners have designed a new clinical study to explore whether antibody-based therapy can prevent or slow cognitive decline in patients with GBA1-related Parkinson's disease. The study is currently ongoing, and we are awaiting the final results.

For me, this type of research is crucial as it reflects a paradigm shift in disease-modifying therapies: we have moved beyond simply asking whether there is a single drug that can treat all forms of Parkinson's disease, and are now asking whether we can identify more targeted treatments for specific pathological subtypes.

The clinical symptoms are similar.

This does not mean that the same treatment should be accepted.

Previously, I discussed three distinct types of Parkinson's disease: those directly associated with alpha-synuclein, GBA1-related Parkinson's disease, and LRRK2-related Parkinson's disease.

They all produce the clinical manifestations we term "Parkinson's disease," with overlap between motor and non-motor symptoms, although the underlying pathological mechanisms are not entirely identical.

This is the point I most want to emphasize today: we need different types of treatment because the underlying disease mechanisms vary among patients. While clinical symptoms may be identical, the pathological mechanisms can be entirely different.

Traditional Mendelian genetics can explain only part of the picture. In fact, for the vast majority of Parkinson's disease cases, the complete etiology remains unknown.

Whole-genome studies are continually expanding our understanding. By comparing individuals with Parkinson's disease to healthy controls across diverse global populations, more than 130 associated genetic loci have been identified to date, and this number continues to rise.

Among these genetic loci are also the important genes mentioned earlier, including SNCA, LRRK2, and GBA1.

Thus, we are now increasingly recognizing that Parkinson's disease has a highly complex genetic architecture. It encompasses not only a few potent pathogenic mutations but also numerous weaker risk variants that can act cumulatively; it involves both coding-region variants and non-coding regions affecting gene expression regulation.

Moreover, genes do not act in isolation; they interact with environmental factors. For instance, trauma, exposure to pesticides or other toxins, as well as certain lifestyle factors mentioned earlier, may all play a role.

Approximately 25% to 30% of Parkinson's disease cases are linked to genetic factors, yet much remains unknown. Environmental factors may also play a role, and there could be disease-causing mechanisms that have not yet been identified.

In conclusion, the genetic evidence we have discussed today tells us that Parkinson's disease does not follow a single path to onset.

Abnormalities in alpha-synuclein, vesicle sorting and transport, lysosomal function, and other cellular pathways may all contribute to disease pathogenesis. These factors interact with one another; sometimes a single high-impact mutation predominates, while at other times multiple weaker genetic risks cumulatively converge.

Both familial and sporadic Parkinson's disease involve distinct genetic combinations.

Therefore, the first question we must address in the future is a very specific one: What exactly is the disease mechanism underlying this patient's condition?

Only by understanding the specific pathogenic mechanisms and genetic background can we proceed to develop a more appropriate treatment plan for him, including disease-modifying therapies that can truly alter the course of the disease.

Finally, I would like to thank all our partners and the funders who have supported this research, and I also appreciate everyone's time and attention.

(This excerpt is from Thomas Gasser's presentation at the 2026 Zhangjiang Pharma Valley Conference and Shanghai International Biomedical Industry Week, specifically the frontier session titled "New Paradigms in Parkinson's Disease Treatment".)Full Text of the Speech Above)