- Parkinson’s disease is a disease that affects the nerves of the brain and, therefore, affects movement.
- People with Parkinson’s disease may also experience cognitive changes and have difficulty with daily activities.
- Research is underway into the specific components of Parkinson’s disease and actions that could help treat the disease.
- A study has found that disrupting the interaction between two proteins could be key to blocking neurodegeneration in Parkinson’s disease.
Parkinson’s disease is a complex disease that affects nerve function. Researchers are still trying to understand the brain changes that occur in this disease and what actions might prevent these changes from occurring.
One area of interest is examining the mechanisms that contribute to the accumulation of alpha-synuclein protein clumps in the brain of a person with Parkinson’s disease.
A study published in Natural communicationsfound that two key proteins, Lag3 and Aplp1, interact to facilitate alpha-synuclein toxicity.
Researchers also found that using an anti-lag3 antibody disrupts this protein interaction and helps stop neurodegeneration in mice.
If future research aligns with these findings, it could indicate a potential way to stop the progression of Parkinson’s disease.
The researchers used mice to further examine what is involved in the abnormal pathway of alpha-synuclein. They were able to confirm that two key proteins are involved: Aplp1 and Lag3.
They discovered that the interaction between these two proteins contributes to “the binding, internalization, transmission and toxicity of disease agents (alpha-synuclein)”. The results also suggest that Aplp1 and Aplp1-Lag3 interaction contributes to cell-to-cell transmission of alpha-synuclein.
The research further confirmed that genetic deletion of Aplp1 and Lag3 helped preserve dopamine neurons – brain cells that release dopamine, the hormone whose production is impaired in Parkinson’s disease – and eliminate behavioral deficits of fibrils preformed by alpha-synuclein.
Study authors Xiaobo Mao, Ph.D., Ted M. Dawson, and Valina L. Dawson summarized some of the study’s key findings this way:
“(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 clusters are a hallmark of Parkinson’s disease and are responsible for the progressive loss of dopamine-producing neurons, leading to movement disorders and cognitive impairment.
With this data in mind, the next step was to examine how stopping the interaction between Aplp1 and Lag3 could help resolve alpha-synuclein problems and potentially stop neurodegeneration.
Researchers investigated how using the Lag3 antibody 410C9 could help. They discovered that this antibody was capable of disrupting the Aplp1-Lag-3 interaction. This helped prevent the pathogenesis and transmission of alpha-synuclein, which, in turn, helped prevent neurodegeneration and behavioral deficits.
The data has specific clinical implications since an anticancer drug approved by the Food and Drug Administration (FDA) already targets Lag3.
“The exciting finding is that Lag3 is already the target of an FDA-approved cancer drug called
“By blocking the interaction between Aplp1 and Lag3, (we) found that the anti-Lag3 antibody could prevent the spread of alpha-synuclein clusters in mouse models of Parkinson’s disease. This suggests that repurposing this FDA-approved drug could potentially slow or stop the progression of Parkinson’s disease in humans,” they explained.
Future tests could examine how nivolumab/relatlimab could benefit people with Parkinson’s disease.
This research has some key limitations, mainly in that testing something in mice differs from testing something in humans.
The researchers were also limited by the nature of their specific work, the procedures they used, and the effectiveness of the type of mice they used in this research.
The study authors also acknowledge that Aplp1 might promote Lag3 action through something other than direct interaction, so further research is needed in this area. They also want to further examine the physiological role of Aplp1 and Lag 3 and how these proteins may work with other 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 authors of the study noted the following stages of further research:
“The next steps would be to conduct clinical trials with the anti-Lag3 antibody 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 evaluate the drug’s potential as a treatment for these neurodegenerative diseases. Additionally, (we) plan to first study ways to prevent unhealthy brain cells from releasing pathogenic alpha-synuclein clumps, which could complement the approach of blocking their spread and uptake by healthy cells.
These Lewy bodies are clumps of alpha-synuclein proteins that accumulate inside brain cells. People with Parkinson’s disease may experience movement difficulties such as tremors, imbalance, and gait changes. They may also have trouble remembering or paying attention to certain things.
Currently, Parkinson’s disease does not die without a cure, so treatment focuses largely on relieving symptoms. This may include therapy to help with movement and speech, dietary changes, and the use of medications to help with movement difficulties.
Daniel Truong, MD, a neurologist and medical director of the Truong Neuroscience Institute at MemorialCare Orange Coast Medical Center in Fountain Valley, Calif., who was not involved in the recent study, explained a little more about how Parkinson’s disease affects the body.
“Parkinson’s disease affects people in different ways. The disease presents with motor and non-motor symptoms as we currently know it. Motor symptoms cause tremors, rigidity, bradykinesia (slowness of movements), and falls. These symptoms can seriously affect daily activities and independence. Falls are most often the cause of death,” he said. Medical News Today.
“Non-motor 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 decreased quality of life (and) increased dependence on caregivers, leading to emotional and financial problems for the patient and their family. It is a progressive disease whose symptoms worsen over time. This causes significant emotional and psychological stress for both patients and their caregivers.
–Daniel Truong, MD