Parkinson’s: Cancer drug halts disease progression in mice

The researchers used mice to look more at what is involved in the abnormal alpha-synuclein journey. They were able to confirm that two key proteins are involved: Aplp1 and Lag3.

They found that the interaction between these two proteins contributes to the “binding, internalization, transmission, and toxicity of pathologic [alpha-synuclein].” The findings also suggest that Aplp1 and Aplp1-Lag3 interaction contribute to alpha-synuclein’s cell-to-cell transmission.

The research further supported that the genetic deletion of Aplp1 and Lag3 helped preserve dopaminergic neurons — brain cells that release dopamine, the hormone whose production is impaired in Parkinson’s — and eliminate behavior deficits from alpha-synuclein-preformed fibrils.

Study authors Xiaobo Mao, Ph.D., Ted M. Dawson, and Valina L. Dawson summarized some of the key findings of the study thus:

“[Our team] at Johns Hopkins discovered that two proteins, called Aplp1 and Lag3, play an important role in the spread of Parkinson’s disease in the brain. These proteins interact with each other and allow harmful clumps of another protein called alpha-synuclein to enter and kill healthy brain cells. Alpha-synuclein clumps are a hallmark of Parkinson’s disease and are responsible for the progressive loss of dopamine-producing neurons, leading to movement and cognitive impairments.”

With these data in mind, the next step was to look at how stopping the interaction between Aplp1 and Lag3 could help with alpha-synuclein problems and potentially stop neurodegeneration.

The researchers investigated how using the Lag3 antibody 410C9 could help. They found that this antibody was able to disrupt the Aplp1-Lag-3 interaction. This helped prevent alpha-synuclein pathogenesis and transmission, which, in turn, helped prevent neurodegeneration and behavioral deficits.

The data has specific clinical implications since a Food and Drug Administration (FDA)-approved cancer drug already targets Lag3.

“The exciting discovery is that Lag3 is already the target of an FDA-approved cancer drug called nivolumab/relatlimab, which uses antibodies to block the activity of Lag3,” the study authors told Medical News Today.

“By blocking the interaction between Aplp1 and Lag3, [we] found that anti-Lag3 antibody could prevent the spread of alpha-synuclein clumps in mouse models of Parkinson’s disease. This suggests that repurposing this FDA-approved drug could potentially slow or halt the progression of Parkinson’s disease in humans,” they explained.

Future testing could look into testing how nivolumab/relatlimab could benefit people with Parkinson’s disease.

This research has some key limitations, primarily in that testing something in mice differs from testing something in people.

The researchers were also limited by the nature of their specific work, the procedures they used, and the effectiveness of using the type of mice they used in this research.

The study authors also acknowledge that Aplp1 could promote Lag3’s action through something other than direct interaction, so more research is required in this area. They also want to look more at the physiological role of Aplp1 and Lag 3 and how these proteins may work with additional cell types.

There are opportunities for future research in this area, which could ultimately lead to better outcomes for people with Parkinson’s disease. The study authors noted the following steps of continued research:

“The next steps would involve conducting clinical trials with the anti-Lag3 antibody drug in mouse models of Parkinson’s and Alzheimer’s diseases to further evaluate its efficacy and safety. If successful, human clinical trials would follow to assess the drug’s potential as a treatment for these neurodegenerative diseases. Additionally, [we] plan to investigate ways to prevent unhealthy brain cells from releasing disease-causing alpha-synuclein clumps in the first place, which could complement the approach of blocking their spread and uptake by healthy cells.”

Parkinson’s disease affects the brain and movement. One characteristic brain change in Parkinson’s disease is the presence of Lewy bodies.

These Lewy bodies are clumps of alpha-synuclein protein that build up inside brain cells. People with Parkinson’s disease can experience movement difficulties such as tremors, imbalance, and gait changes. They may also struggle to remember things or pay attention.

Currently, Parkinson’s disease dies not have a cure, so treatment focuses largely on symptom relief. It can include therapy to help with movement and speech, dietary changes, and the use of medications to help address movement struggles.

Daniel Truong, MD, neurologist and medical director of the Truong Neuroscience Institute at MemorialCare Orange Coast Medical Center in Fountain Valley, CA, who was not involved in the recemt study, explained a little more about how Parkinson’s disease affects the body.

“Parkinson’s disease impacts people in different ways. The disease has motor and nonmotor symptoms as we know now. The motor symptoms cause tremors, rigidity, bradykinesia (slowness of movement), and falling. These symptoms can severely affect daily activities and independence. Falling is most often the cause of death,” he told Medical News Today.

“The nonmotor symptoms cause cognitive decline, mood disorders (such as depression and anxiety), sleep disturbances, and autonomic dysfunction (e.g., constipation, urinary problems). These symptoms lead to declined quality of life [and] increased dependence on care givers, resulting in emotional and financial problems for patient and family. It is a progressive condition with symptoms [that] worsen over time. It has significant emotional and psychological stress for both patients and their caregivers.”

– Daniel Truong, MD