Potential Parkinson’s Treatment Found Among FDA-Approved Drugs

Scientists have uncovered a significant discovery involving a cell surface protein known as Aplp1, which facilitates the spread of Parkinson’s disease-related material between brain cells.

Excitingly, experiments with mice have revealed that an FDA-approved cancer drug targeting Lag3, another protein interacting with Aplp1, effectively blocks this spread, suggesting a potential therapy may already be available.

In a recent study, an international team of researchers detailed how Aplp1 collaborates with Lag3 to assist harmful alpha-synuclein protein clusters in entering brain cells.

“Now that we understand the interaction between Aplp1 and Lag3, we have gained new insights into how alpha-synuclein contributes to the progression of Parkinson’s disease,” explained Xiaobo Mao, a neuroscientist from Johns Hopkins University in the US. “Our findings indicate that targeting this interaction with drugs could significantly slow down the advancement of Parkinson’s disease and other neurodegenerative disorders.”

Parkinson’s disease affects over 8.5 million people worldwide, ranking as the second most prevalent neurodegenerative condition after Alzheimer’s disease.

Characterized by progressive movement impairments, Parkinson’s is typically diagnosed based on the manifestation of symptoms such as tremors, stiffness, balance issues, speech difficulties, disrupted sleep patterns, and mental health challenges. As an incurable disease, it often leads to difficulties in walking and speaking for patients.

The symptoms of Parkinson’s arise predominantly from the loss or dysfunction of dopamine-producing neurons in the substantia nigra region of the brain, crucial for fine motor control. This neuronal degeneration is believed to be triggered by Lewy bodies—abnormal protein clumps primarily composed of misfolded alpha-synuclein—that propagate between neurons.

Alpha-synuclein ordinarily facilitates proper neuronal communication but becomes problematic when it misfolds and forms insoluble aggregates. However, distinguishing whether this protein misfolding is a cause or consequence of Parkinson’s disease remains challenging.

Previous studies on mice indicated that Lag3 binds to alpha-synuclein proteins, propagating Parkinson’s pathology among neurons. While deleting Lag3 significantly hindered this process, it did not entirely halt it, suggesting involvement of another protein in the neuronal uptake of misfolded alpha-synuclein.

“Our previous work showed that Lag3 is not the sole cell surface protein aiding in alpha-synuclein absorption by neurons, leading us to explore Aplp1 in our recent experiments,” noted Valina Dawson, a neuroscientist at Johns Hopkins University.

In their experiments with genetically modified mice lacking Aplp1, Lag3, or both proteins, the researchers observed that each protein independently facilitates the absorption of harmful alpha-synuclein by brain cells, with their combined presence markedly enhancing uptake.

Mice lacking both Aplp1 and Lag3 exhibited a 90% reduction in the entry of harmful alpha-synuclein into healthy brain cells, indicating significantly greater blockage of protein clump formation compared to mice lacking only one protein.

Furthermore, when normal mice were administered nivolumab/relatlimab—a melanoma drug containing a Lag3 antibody—it disrupted the interaction between Aplp1 and Lag3, nearly completely preventing the formation of disease-causing alpha-synuclein clumps in neurons.

“The anti-Lag3 antibody effectively halted further spread of alpha-synuclein seeds in our mouse models and showed superior efficacy compared to Lag3 depletion alone, due to the close association between Aplp1 and Lag3,” explained Ted Dawson, a neuroscientist also from Johns Hopkins University.

Moving forward, the researchers plan to test the Lag3 antibody in mouse models of Parkinson’s disease and Alzheimer’s disease, where Lag3 has also been identified as a potential therapeutic target.