Breakthrough in Parkinson’s Treatment: Scientists Discover Protein Link and an FDA-Approved Drug That Blocks It

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting over 8.5 million people worldwide, with no cure currently available. However, a groundbreaking new study has uncovered a critical mechanism behind the disease’s progression—and, remarkably, an existing FDA-approved drug that could stop it.

Scientists have discovered that two key proteins, Aplp1 and Lag3, act like helpers in spreading toxic alpha-synuclein clumps—the sticky proteins that are a major cause of Parkinson’s disease—through the brain. Even more exciting, researchers found that the cancer immunotherapy drug nivolumab combined with relatlimab—which targets a protein called Lag3—was able to block this harmful interaction in mice. As a result, it stopped the disease from getting worse.

Understanding Parkinson’s Disease and Alpha-Synuclein

What Causes Parkinson’s?

Parkinson’s disease is characterized by the loss of dopamine-producing neurons in the brain, leading to symptoms like tremors, muscle stiffness, slow movement, and balance problems.

The root cause is misfolded alpha-synuclein proteins, which clump together into Lewy bodies, spreading from cell to cell and killing neurons.

How Does Alpha-Synuclein Spread?

Recent research shows that alpha-synuclein behaves like a prion—a misfolded protein that corrupts healthy versions of itself. It moves through the brain via neuron-to-neuron transmission, binding to cell surface receptors, and seeding new clumps in healthy cells.

Until now, the exact mechanisms were unclear. But this new study reveals two proteins that act as accomplices in this deadly spread.

The Key Players: Aplp1 and Lag3

Aplp1: The Toxic Protein Binder

Amyloid β precursor-like protein 1 (Aplp1) is a cell surface protein that binds strongly to alpha-synuclein fibrils, helps anchor them to neurons, and belongs to the same family as amyloid precursor protein (APP), linked to Alzheimer’s.

Lag3: The Entry Gate for Disease

Lymphocyte-activation gene 3 (Lag3) is an immune checkpoint protein that acts as a receptor for alpha-synuclein uptake, works with Aplp1 to accelerate disease spread, and is already targeted by cancer immunotherapies.

The Deadly Partnership

The study found that Aplp1 grabs onto toxic alpha-synuclein clumps, Lag3 pulls them into healthy neurons, and once inside, they corrupt normal proteins, forming new clumps.

When researchers blocked either protein in mice, alpha-synuclein spread dropped by up to 90 percent.

The Game-Changer: An Existing Drug That Blocks Lag3

Nivolumab/Relatlimab: A Cancer Drug with Parkinson’s Potential

This immunotherapy, used for melanoma and other cancers, works by inhibiting Lag3. The study showed it prevents alpha-synuclein from entering neurons, protects dopamine-producing cells, and reduces motor and cognitive decline in mice.

Why This Matters

There is no need for new drug development—repurposing speeds up approval. It could actually slow down or even halt the progress of Parkinson’s disease, instead of just hiding the symptoms like most current treatments do. It could also help with Alzheimer’s and Lewy body dementia, which involve similar protein clumps.

Implications for Future Parkinson’s Treatment

Next Steps: Human Trials

Before this treatment reaches patients, researchers must confirm safety and efficacy in humans, determine optimal dosing, and identify which patients benefit most.

Expert Opinions

Dr. Ted Dawson from Johns Hopkins said, “This is one of the most exciting breakthroughs in Parkinson’s research. If human trials succeed, we could have a disease-modifying therapy within a decade.”

Dr. Rebecca Gilbert from the American Parkinson Disease Association added, “Repurposing existing drugs is a smart strategy—it could cut years off the usual timeline.”

Challenges Ahead

Key questions remain: Will the drug work as well in humans? Could long-term use cause side effects? Will it help advanced-stage patients, or only early cases?

The Science Behind Protein Misfolding in Neurodegenerative Diseases

Understanding Protein Aggregation

Many brain diseases happen because proteins fold the wrong way and build up, damaging brain cells. In Parkinson’s disease, the alpha-synuclein protein undergoes conformational changes that lead to:

Formation of oligomers (small clusters)
Development of fibrils (long, thread-like structures)
Creation of Lewy bodies (larger aggregates)

These abnormal protein structures exhibit prion-like behavior, capable of:

Self-propagation through templated misfolding
Cell-to-cell transmission
Spreading along neural pathways in a predictable pattern

The Prion Hypothesis in Parkinson’s

The prion-like spread of alpha-synuclein explains several clinical observations:

Braak staging of Parkinson’s pathology
The gut-to-brain hypothesis of disease origin
The appearance of Lewy bodies in transplanted neurons

Recent cryo-EM studies have revealed multiple strains of alpha-synuclein fibrils, which may account for the clinical variability seen in Parkinson’s patients.

Detailed Mechanism of Aplp1-Lag3 Interaction

Structural Biology Insights

X-ray crystallography and cryo-EM studies show:

Aplp1’s extracellular domain contains specific binding pockets for alpha-synuclein fibrils
Lag3 connects with Aplp1 by linking up through their outer cell surfaces, forming a stable pair across the cell membrane.
The binding interface shows high affinity for pathological alpha-synuclein but not normal monomers

Step-by-Step Transmission Process

Pathological alpha-synuclein fibrils bind to Aplp1’s extracellular domain
Aplp1 undergoes conformational change, exposing Lag3 binding sites
The Aplp1-Lag3 complex internalizes via clathrin-mediated endocytosis
Once inside the cell, alpha-synuclein seeds corrupt native proteins
New aggregates are exported via exosomes or tunneling nanotubes

Preclinical Evidence from Animal Models

Mouse Study Results

The original study published in Nature used:

Wild-type mice injected with alpha-synuclein preformed fibrils (PFFs)
Aplp1 knockout mice
Lag3 knockout mice
Double knockout (Aplp1/Lag3) mice

Key findings included:

80-90% reduction in alpha-synuclein spread in knockouts
Preservation of dopaminergic neurons in substantia nigra
Improved motor performance on rotarod and pole tests
Reduced microglial activation and neuroinflammation

Long-Term Effects

Six-month follow-up showed:

Knockout mice maintained cognitive function
No compensatory upregulation of other uptake mechanisms
Sustained protection against neurodegeneration

Nivolumab/Relatlimab: From Cancer to Neurology

Mechanism of Action in Oncology

As an immune checkpoint inhibitor:

Blocks Lag3 on T-cells, enhancing anti-tumor immunity
Shows efficacy in metastatic melanoma
FDA-approved combination therapy

Repurposing for Parkinson’s

The study demonstrated:

70% reduction in alpha-synuclein uptake at therapeutic doses
Penetration of blood-brain barrier (confirmed by mass spectrometry)
Favorable safety profile in CNS tissue

Comparative Advantages Over Existing Therapies

Current Parkinson’s treatments (L-DOPA, dopamine agonists) only address symptoms. This approach:

Targets root cause of neurodegeneration
May slow or stop disease progression
Could be combined with existing symptomatic treatments

Potential Clinical Applications

Patient Stratification

Potential biomarkers for treatment response:

CSF alpha-synuclein levels
Lag3 expression on circulating immune cells
Aplp1 genetic variants

Treatment Protocols

Possible administration routes:

Intravenous infusion (current cancer protocol)
Intrathecal delivery for enhanced CNS penetration
Oral formulations in development

Combination Therapies

Could be paired with:

Alpha-synuclein clearance enhancers
Neuroprotective agents
Anti-inflammatory drugs