FDA-Approved Cancer Drug Shows Potential in Targeting Protein Responsible for Parkinson’s Disease Progression

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In studies involving genetically engineered mice, a team of experts reported the identification of a key protein involved in Parkinson's disease.

What Causes Parkinson's Disease?

Parkinson's disease (PD) refers to a progressive movement disorder that affects the human nervous system and the parts of the body that are controlled by the nerves. It is considered the second most common neurodegenerative disease after Alzheimer's disease.

This medical condition is usually diagnosed only when symptoms show, like speech difficulties, balance problems, mental health issues, tremors, disturbed sleep patterns, and stiffness. Parkinson's disease remains incurable, so having this disease means a patient may struggle to speak or walk.

The symptoms of Parkinson's disease mostly result from the impairment or death of neurons that produce dopamine. This type of neuron is found in the substantia nigra, a region in the brain that is responsible for fine motor control. The damage to these neurons is thought to be caused by Lewy bodies or the abnormal clumps of proteins called alpha-synuclein.

Alpha-synuclein is the protein that maintains communication between neurons. Problems arise when this protein becomes insoluble or misfolded.

Novel Therapeutic Target for Parkinson's Disease

In a recent study, a team of experts from Johns Hopkins Medicine claimed that they have identified a new biological target that drives the spread of Parkinson's disease-causing alpha-synuclein. The details of their research are described in the paper "Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein."

Led by Xiaobo Mao, the scientists focused on a cell surface protein known as Aplp1, which was found to connect with another cell surface receptor called Lag3. This receptor plays an important role in spreading harmful alpha-synuclein proteins to brain cells. Additionally, its buildups are considered hallmarks of Parkinson's disease.

Prior studies revealed that Lag3 binds to alpha-synuclein proteins and spreads the pathology of Parkinson's disease in neurons. Therefore, targeting this interaction with drugs may slow the progression of PD and other neurodegenerative diseases.

According to the researchers, Lag3 is currently the target of an FDA-approved combination drug that uses antibodies to instruct the immune system what to find and destroy. This means that a potential therapy against Parkinson's disease may already exist.

To confirm this hypothesis, the researchers conducted tests with genetically modified mice missing either Aplp1 or Lag3, or both. It was found that Aplp1 or Lag3 can independently help brain cells absorb harmful alpha-synuclein. Together, these proteins may significantly increase the uptake.

The mice missing both Aplp1 and Lag3 have 90% less alpha-synuclein entering their healthy brain cells. This indicates that a greater amount of the protein clumps were blocked with both proteins than with just one.

Meanwhile, the normal mice were given the drug nivolumab/relatlimab, a type of drug which contains a Lag3 antibody. The research team discovered that the medication also stopped the interaction of Aplp1 and Lag3, almost completely preventing the formation of alpha-synuclein clumps in neurons.

Mao and colleagues concluded that the anti-Lag3 antibody was successful in blocking the spread of disease-causing alpha-synuclein seeds in the mouse models. It also showed better efficacy than Lag3-depletion due to the close association between Aplp1 and Lag3.