Understanding Parkinson's Disease: New Insights into Protein Interactions and Therapeutic Targets

Authors: Elles Zwikker¹, Sanne Zwikker²

¹Independent Scholar, USA

²Department of Biology, University of Rochester, Rochester NY, USA

zwikker.elles@gmail.com , szwikker@u.rochester.edu

Scientific Abstract

Background: Parkinson's disease affects over 10 million people globally and represents one of the most prevalent incurable neurological disorders. The disease results from progressive neurodegeneration in the substantia nigra, leading to dopamine depletion and motor dysfunction. Understanding the molecular mechanisms underlying disease progression is critical for developing effective therapeutic interventions.

Objective: This literature review examines recent discoveries regarding the molecular mechanisms of alpha-synuclein (α-synuclein) propagation in Parkinson's disease, with particular focus on the interaction between APLP1 (Amyloid precursor-like protein 1) and LAG3 (Lymphocyte-activation gene 3) as facilitators of pathological protein transmission.

Key Findings: Recent 2024 research identified APLP1 and LAG3 as co-receptors that mediate neuronal uptake of misfolded α-synuclein. LAG3 selectively binds to fibrillar α-synuclein but not to normal soluble forms, while APLP1 strengthens this binding, stabilizes the receptor complex, and accelerates cellular uptake. The proteins interact through specific structural domains (APLP1-E1 with LAG3-D2/D3), with a conserved seven-amino acid sequence critical for function.

Therapeutic Implications: Disrupting the APLP1-LAG3 interaction represents a promising disease-modifying strategy that specifically targets pathological mechanisms while preserving normal cellular functions. FDA-approved LAG3-targeting cancer immunotherapies could potentially be repurposed for Parkinson's disease, significantly accelerating the path to clinical application. The therapeutic approach offers flexibility through multiple intervention points: targeting APLP1, LAG3, their interaction, or α-synuclein binding to the complex.

Conclusions: The APLP1-LAG3 partnership provides a concrete molecular mechanism explaining cell-to-cell transmission of α-synuclein pathology in Parkinson's disease. Blocking this interaction prevents neurodegeneration in preclinical models, offering a clear roadmap for developing treatments that could slow or halt disease progression. While human applicability, optimal treatment timing, and long-term safety require further investigation, these findings represent a significant advance toward disease-modifying therapies for Parkinson's disease.

Keywords: Parkinson's disease, alpha-synuclein, APLP1, LAG3, neurodegeneration, protein propagation, therapeutic antibodies, disease-modifying therapy

Introduction to Parkinson's Disease

Parkinson's disease is a progressive neurological disorder that affects movement, balance, and coordination. The condition develops when nerve cells in the substantia nigra of the brain become damaged or die, resulting in decreased dopamine production. Dopamine is a chemical messenger essential for controlling muscle movement and emotional responses.

Parkinson's disease represents one of the most prevalent incurable neurological disorders worldwide. More than 10 million people globally live with this condition, and over 90,000 new cases are diagnosed annually in the United States alone. The disease impacts every bodily function controlled by the brain, creating widespread effects on patients' quality of life.

Recent research published in 2024 identified a critical mechanism underlying the progression of Parkinson's disease. Scientists discovered that the interaction between two brain proteins, APLP1 and LAG3, facilitates cellular uptake of misfolded alpha-synuclein (α-synuclein). Misfolded α-synuclein blocks the interactions of neurons, resulting in cell death. Non-functioning neurons lead to symptoms such as tremors, slowness of movement, and rigidity. This finding suggests that disruption of the APLP1–LAG3 interaction could potentially be a therapeutic strategy to slow the progression of Parkinson’s disease. This finding is a major scientific breakthrough, opening doors for alternative treatments.

Alpha-Synuclein in Parkinson's Disease

   Normal Function

α-Synuclein is a protein primarily located in the brain, specifically in motor regions, which helps regulate movement. Under healthy conditions, α-synuclein performs important functions in communication between brain cells and regulation of neurotransmitters, the chemical messengers that transmit signals throughout the nervous system.

   Disease Mechanism

Problems arise when α-synuclein misfolds and twists into an abnormal shape. These misfolded proteins tend to stick together, forming toxic aggregations known as Lewy bodies and Lewy neurites (Whyte, 2023). As the protein clumps accumulate, they disrupt normal cellular function and cause neuron death.

   Target Neurons

The toxic protein clumps predominantly form in dopaminergic neurons, which are specialized cells responsible for producing dopamine. These neurons are concentrated in the substantia nigra, a region located in the midbrain that initiates and controls voluntary movements in smooth coordination and precise initiation.

These dopaminergic neurons release dopamine to the striatum, a nearby brain region. The striatum uses this dopamine signal to help coordinate smooth and voluntary movements. This connection between the substantia nigra and the striatum is essential for starting and regulating motion. When this pathway is disrupted, such as by the buildup of misfolded α-synuclein, dopamine signaling decreases. As a result, individuals may experience movement-related symptoms typical of Parkinson’s disease, including tremors, muscle stiffness, and slowed movements.

LAG3: From Immune Function to Brain Disease

   Primary Function

LAG3 (Lymphocyte-activation gene 3) is a receptor protein located on the surface of certain cells. Its primary role is in immune system regulation, where it signals to immune cells such as T cells (specialized white blood cells) to reduce or cease activity (Chocarro, 2021). This regulatory function prevents the immune system from overreacting or attacking the body's own tissues.

   Discovery in the Brain

In 2016, researchers first reported LAG3 expression on neurons, though its specific role in the brain remained unclear. Subsequent studies revealed LAG3’s significance in the development of neurodegenerative diseases. Specifically in Parkinson's disease, LAG3 binds to misfolded α-synuclein proteins, facilitating their entry into neurons.

   Selective Binding

An important characteristic of LAG3 is its selectivity. Healthy α-synuclein exists as flexible, soluble molecules that float freely without clumping. LAG3 does not recognize or bind to this normal form because it lacks the structural features LAG3 targets. Misfolded α-synuclein, however, forms fibrils—long, sticky strands that aggregate together. These α-synuclein clumps present a specific surface pattern that LAG3 recognizes and binds to with high affinity, causing the introduction of misfolded α-synuclein into the cell.

The Mechanism of Toxicity: How LAG3 Facilitates Disease Progression

   Cellular Uptake

When LAG3 binds to misfolded α-synuclein on the neuron's surface, it results in endocytosis (cellular uptake). Through this mechanism, the toxic protein is pulled into the neuron. Once inside, the misfolded α-synuclein encounters normal α-synuclein molecules. Misfolded proteins bind to healthy α-synuclein molecules and induce conformational changes, converting them into similarly toxic, misfolded forms.

   Propagation of Damage

These newly misfolded proteins adhere to one another, forming increasingly larger aggregations of fibrils. Eventually, these clusters grow into Lewy bodies, structures that interfere with cellular operations. Protein clumps block critical cellular systems, most notably disrupting the neuron's ability to produce and utilize energy.

Neurons are high-energy cells that require constant power to transmit signals, maintain connections, and perform self-repair. When energy production fails, neurons die. The loss of these cells interrupts chemical signaling pathways involving dopamine and other neurotransmitters, resulting in the brain's loss of control over various functions including movement, cognition, and emotional regulation.

   Spreading Pattern

As neurons deteriorate, the connected neurons also fail, spreading the damage throughout neural networks. This cell-to-cell transmission pattern explains the progressive nature of Parkinson's disease and its gradual negative impact on multiple brain regions over time.

APLP1: A Critical Partner in Disease Progression

   Protein Identity

APLP1 (Amyloid precursor-like protein 1) is a surface protein found on neurons. It belongs to a family of proteins that facilitate cell communication, support synapse function (the junctions where neurons connect and transmit signals), and contribute to brain development and repair. APLP1 performs distinct functions primarily focused on maintaining neuronal connectivity and health.

   Role in Disease

The 2024 Johns Hopkins study made a groundbreaking discovery: APLP1 acts as a co-receptor that enhances LAG3's ability to capture and internalize misfolded α-synuclein. APLP1 performs three critical functions:

• Strengthens binding: APLP1 reinforces LAG3's grip on misfolded α-synuclein.

• Stabilizes interaction: The APLP1–LAG3 protein complex becomes more stable, creating a recognizable structure that toxic α-synuclein can identify and bind to. This stability increases the likelihood of attachment and internalization through processes like endocytosis.

• Accelerates uptake: The process occurs more rapidly, leading to increased internalization and faster disease spread.

   How the Proteins Connect

Research revealed that APLP1 and LAG3 bind to one another in specific regions of their structure. Scientists identified the exact spots where these proteins connect on the surface of neurons, forming a combined receptor complex that works together.

• The Connection Points: Proteins are made up of different sections, each with specific jobs. APLP1 has a section called E1, and LAG3 has two sections called D2 and D3. These are simply names scientists use to identify different parts of the proteins. The E1 section of APLP1 physically attaches to the D2 and D3 sections of LAG3. This is where the two proteins grip each other to form their partnership.

• The Matching Pattern: This connection is not random. Within these connecting sections, both proteins contain a matching short sequence made of seven building blocks (amino acids). This matching sequence appears to be essential for their ability to bind and internalize the toxic, misfolded α-synuclein. Without this precise connection between APLP1's E1 section and LAG3's D2 and D3 sections, the toxic proteins have a much harder time entering neurons.

Key Research Findings

   Experimental Evidence

The 2024 study employed multiple experimental approaches to characterize the APLP1–LAG3 interaction and its role in disease:

• Binding Studies: Researchers demonstrated that misfolded α-synuclein binds specifically to APLP1 with high affinity (a binding strength of 430 nanomolar), while normal α-synuclein shows no appreciable binding. Together, APLP1 and LAG3 account for more than 40% of pathological α-synuclein binding to neurons.

• Cellular Uptake: When both APLP1 and LAG3 were deleted from neurons, internalization of misfolded α-synuclein was reduced by approximately 70% compared to normal neurons. This demonstrates that the combined effect of the two proteins exceeds what either does individually.

• Disease Transmission: When both proteins were deleted, the toxic proteins remained trapped in the initial neurons and failed to propagate to neighboring cells. This effectively eliminated the domino effect that causes Parkinson's disease to progressively spread throughout brain networks.

Preclinical Testing and Conclusions

In a 2024 preclinical study, scientists explored the effects of blocking interactions between APLP1 and LAG3. They used genetically engineered mice to test a clearly defined experimental endpoint. Misfolded alpha-synuclein was injected into two groups of mice: one with normal APLP1 and LAG3 function and one with disrupted interaction. The researchers compared the outcomes and found compelling evidence that these proteins play a critical role in the development and spread of Parkinson’s-related pathology.

Mice with APLP1 and LAG3 (normal mice):

• Experienced significant death of dopaminergic neurons

• Developed motor impairments, showing difficulty with movement coordination in pole tests and cylinder tests

• Accumulated high levels of toxic protein clumps throughout the brain

• Showed severe dopamine depletion in the striatum

Mice without APLP1 and LAG3 (both proteins deleted):

• Showed extensive preservation of dopaminergic neurons, meaning most brain cells survived

• Maintained normal motor function despite exposure to the toxic protein

• Had more than 90% reduction in toxic protein accumulation throughout the brain

• Maintained normal dopamine levels in the striatum

Additionally, the scientists found that mice with only APLP1 deleted (LAG3 still present) showed moderate protection, with approximately a 60% reduction in toxic protein buildup. However, deleting both proteins together provided near-complete protection. These mouse studies demonstrate that APLP1 and LAG3 are essential drivers of Parkinson's-like disease progression. Without both proteins, mice remained protected from neuronal damage and motor impairments despite exposure to toxic α-synuclein.

Therapeutic Implications

The research suggests that disrupting the interaction between APLP1 and LAG3 represents a promising therapeutic strategy. By preventing these proteins from working together, it may be possible to significantly reduce the spread of misfolded α-synuclein and slow disease progression.

This targeting strategy offers multiple advantages. It specifically attacks the disease mechanism rather than disrupting normal cellular functions, potentially reducing side effects. The approach offers therapeutic flexibility by allowing treatments to target APLP1, LAG3, or their interaction. Additionally, it can be delivered through minimally invasive methods such as injections, avoiding the need for surgery. Most importantly, it interrupts the cell-to-cell transmission that allows Parkinson’s disease to progressively spread through the brain.

Antibody Therapy Testing

This same study tested an experimental antibody called 410C9 that specifically targets LAG3. This antibody disrupts the APLP1–LAG3 interaction and produces substantial protective effects. The 410C9 antibody binds to a specific region of LAG3 where APLP1 normally attaches. By blocking this connection site, the antibody prevents the two proteins from forming their receptor complex, thereby stopping toxic α-synuclein from entering neurons.

Mice treated with the 410C9 antibody showed significant reduction in dopaminergic neuron loss, decreased accumulation of pathological α-synuclein throughout the brain (greater than 90% reduction), preservation of dopamine and related chemical markers, improved motor function in behavioral tests, and reduced internalization of toxic proteins into neurons.

While 410C9 is currently a research tool, the study's findings have immediate clinical relevance. 410C9 is a reagent that helps scientists study the interaction of LAG3 with other proteins, such as APLP1, by selectively blocking or labelling these interactions. This enables researchers to better understand the mechanisms by which toxic alpha-synuclein enters neurons, potentially guiding the development of targeted therapies for Parkinson’s disease.

FDA-approved cancer immunotherapy drugs that target LAG3 already exist and are used to treat melanoma and other cancers (Johns Hopkins Medicine, 2024). These medications work by blocking LAG3 to enhance immune responses against tumors. Since these drugs target the same protein implicated in Parkinson's disease, they could potentially be repurposed to disrupt the APLP1–LAG3 interaction and slow neurodegeneration. This possibility significantly accelerates the path to clinical application, as these medications have already been tested for safety in humans and could move more quickly through trials for Parkinson's disease than entirely new drugs would require.

Antibody Post-Progression Testing

In the mouse studies, scientists also experimented with delaying antibody treatment after toxic protein exposure and continued weekly for 180 days. Despite starting after the disease process was initiated, the treatment successfully prevented neurodegeneration and behavioral deficits. This indicates that therapeutic intervention could be effective in patients with early-stage Parkinson’s disease, not only as a preventive measure.

In these animal studies, antibody treatment was initiated one day after introducing pathological α-synuclein and continued weekly for 180 days. This prolonged treatment successfully prevented the neurodegeneration and behavioral deficits that would otherwise have developed, suggesting that therapeutic intervention might be effective even after disease processes have begun.

Scientific Significance

   Mechanistic Understanding

This research deepens our understanding of how Parkinson's disease spreads through the brain. The identification of the APLP1–LAG3 partnership provides a concrete molecular mechanism explaining cell-to-cell transmission of pathology. This moves beyond simply observing that proteins spread and instead explains precisely how that spread occurs.

   Therapeutic Development

The findings provide clear targets for drug development:

• Small molecules that disrupt APLP1–LAG3 binding

• Antibodies that block either protein's function

• Compounds that prevent misfolded α-synuclein from binding to the receptor complex

   Biomarker Potential

The proteins and their interaction might serve as biomarkers for disease progression or treatment response, potentially allowing clinicians to monitor therapeutic efficacy.

Limitations and Future Directions

While promising, this research represents preclinical findings in laboratory models. Several important questions require further investigation:

• Human Applicability: Studies must confirm that these mechanisms operate similarly in human Parkinson's disease

• Treatment Timing: Determining the optimal window for therapeutic intervention in patients

• Long-Term Effects: Evaluating the safety and efficacy of chronic APLP1–LAG3 pathway blockade

• Other Cell Types: Understanding whether these proteins play roles in other brain cells (microglia, astrocytes, oligodendrocytes)

• Related Diseases: Investigating whether similar mechanisms operate in other α-synucleinopathies such as dementia with Lewy bodies or multiple system atrophy

Conclusion

The discovery that APLP1 and LAG3 work together to facilitate the transmission of pathological α-synuclein represents a significant advance in Parkinson's disease research. By identifying a specific molecular mechanism underlying disease progression, this work provides concrete targets for therapeutic intervention.

The demonstration that blocking the APLP1–LAG3 interaction, either through genetic deletion or antibody treatment, can prevent neurodegeneration and behavioral deficits in animal models offers hope for future treatments. The existence of FDA-approved LAG3-targeting drugs developed for cancer therapy suggests that clinical translation might occur relatively rapidly.

While substantial work remains to translate these findings into human therapies, the research provides a clear outline for developing disease-modifying treatments that could slow or halt Parkinson's disease progression by interrupting the spread of toxic proteins through neural networks.

Note: This white paper summarizes research findings published in Nature Communications (2024). Readers interested in detailed methodologies and complete data should consult the original research article: Mao, Xiaobo, et al. “Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.” nature communications, 2024, https://www.nature.com/articles/s41467-024-49016-3.

Works Cited

Mao, Xiaobo, et al. “Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.” nature communications, 2024, https://www.nature.com/articles/s41467-024-49016-3.

Chocarro, Luisa. “Understanding LAG-3 Signaling.” PubMed Central, 17 May 2021, https://pmc.ncbi.nlm.nih.gov/articles/PMC8156499/.

“New Study Suggests Cancer Drug Could Be Used to Target Protein Connection That Spurs Parkinson's Disease.” Johns Hopkins Medicine, June 2024, https://www.hopkinsmedicine.org/news/newsroom/news-releases/2024/06/new-study-suggests-cancer-drug-could-be-used-to-target-protein-connection-that-spurs-parkinsons-disease.

Whyte, Barry. “Alpha-synuclein in neurodegenerative disease | BMG LABTECH.” BMG Labtech, 9 June 2023, https://www.bmglabtech.com/en/blog/alpha-synuclein-in-neurodegenerative-disease/. Accessed 2 November 2025.

Declarations:

Author Contributions: Elles Zwikker conceptualized and drafted the manuscript. Sanne Zwikker contributed to data interpretation and manuscript revision. Both authors approved the final version.

Competing Interests: The authors declare no competing interests.

Funding: Not applicable.

Corresponding Author Email: zwikker.elles@gmail.com