Breakthrough Reveals Potential FDA-Approved Parkinson’s Treatment

Recent investigations have elucidated the mechanisms by which a cell surface protein known as Aplp1 facilitates the propagation of neurotoxic materials associated with Parkinson’s disease from one neuron to another within the cerebral milieu.

Encouragingly, an FDA-sanctioned oncology medication that targets a distinct protein, Lag3—which exhibits a notable interaction with Aplp1—has been shown to inhibit this intercellular dissemination in experimental murine models, indicating that a viable therapeutic avenue may already be available.

In a study published in the preceding year, a multinational consortium of researchers articulates the intricate interplay between these two proteins, which is integral to the uptake of deleterious alpha-synuclein aggregates by neuronal cells.

Neuroscientist Xiaobo Mao from Johns Hopkins University remarked in June, “The elucidation of the Aplp1-Lag3 interaction provides a novel framework for comprehending how alpha-synuclein contributes to the pathogenesis of Parkinson’s disease.” He further emphasized that pharmacological targeting of this interaction could potentially decelerate the progression of both Parkinson’s and other neurodegenerative disorders.

Globally, over 8.5 million individuals are afflicted by Parkinson’s disease, rendering it the second most prevalent neurodegenerative malady, following Alzheimer’s. This progressive ailment, predominantly characterized by motor dysfunctions, is typically diagnosed post-manifestation of symptoms such as tremors, rigidity, and cognitive disturbances.

The degeneration of dopaminergic neurons in the substantia nigra underlies the symptomatic presentation of the disease, with the misfolding of alpha-synuclein implicated in the formation of toxic aggregates known as Lewy bodies.

Furthermore, prior murine studies have demonstrated that Lag3’s binding to alpha-synuclein accelerates the spread of Parkinsonian pathology within neurons. While the ablation of Lag3 substantially mitigates this process, it does not entirely inhibit it, suggesting that additional proteins may also participate in mediating the absorption of misfolded alpha-synuclein within the neuronal framework.

The most recent experiments, employing genetically engineered mice deficient in Aplp1, Lag3, or both, revealed that, while Aplp1 and Lag3 can each independently facilitate the cellular uptake of detrimental alpha-synuclein, their simultaneous presence markedly amplifies this assimilation process. A striking reduction—up to 90 percent—of harmful alpha-synuclein ingress was observed in neurons lacking both proteins, underscoring the essential role of Aplp1.

The administration of the drug nivolumab/relatlimab, a therapeutic for melanoma that contains an antibody targeting Lag3, corroborated the inhibition of Aplp1-Lag3 interactions, effectively stymying the synthesis of pathological alpha-synuclein aggregates in neuronal cells.

At this juncture, the researchers intend to explore the efficacy of the Lag3 antibody in murine models of Parkinson’s disease and Alzheimer’s, the latter of which has also been highlighted as a potential avenue for targeted therapy according to emerging research.

This pivotal research has been disseminated in Nature Communications.

Note: An earlier iteration of this article was published in June 2024.