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A team of researchers from Johns Hopkins University School of Medicine has made a groundbreaking discovery that sheds light on the intricacies of Parkinson’s disease and related disorders known as alpha-synucleinopathies. The study, published in Nature Communications, reveals a critical mechanism involving the interaction between amyloid precursor-like protein 1 (Aplp1) and the lymphocyte-activation gene 3 (Lag3), which facilitates the harmful spread of misfolded alpha-synuclein proteins in the brain.
Alpha-synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), are characterized by the abnormal build-up of twisted fibers, or fibrils, composed of alpha-synuclein protein. These pathologic proteins can move from cell to cell, spreading the disease throughout the nervous system, leading to neuronal death and debilitating symptoms.
Lead researchers Xiaobo Mao, Hao Gu, Donghoon Kim, and their colleagues identify Aplp1 as a receptor on the neuron surface that binds to and promotes the internalization of pathologic alpha-synuclein fibrils. Surprisingly, they discovered that Aplp1 does not work alone but collaboratively with another receptor, Lag3. The study demonstrates that when both Aplp1 and Lag3 are deleted, there is almost a complete blockade of alpha-synuclein-induced cellular death and associated behavioral deficits.
Their experiments involving both cultured neurons and mouse models show that the co-existence of Aplp1 and Lag3 significantly enhances the uptake of pathologic alpha-synuclein, leading to its spread and associated neurotoxicity. Furthermore, a therapeutic antibody targeting Lag3, known as 410C9, was found to disrupt the harmful interaction between Aplp1 and Lag3. Remarkably, administration of 410C9 to mice substantially protected against neurodegeneration triggered by pathologic alpha-synuclein, providing a promising avenue for future therapies.
These findings not only deepen our understanding of Parkinson's disease progression but also bring hope for therapeutic strategies aimed at halting neurodegeneration in such diseases. Targeting the Aplp1-Lag3 pathway could offer a novel approach to treating alpha-synucleinopathies, potentially improving the lives of many affected individuals. The full study can be accessed through the link provided in the article, and the research was built with the help of Buoy Health.
For more information and a closer look at the study: https://doi.org/10.1038/s41467-024-49016-3
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References
Mao, X., Gu, H., Kim, D. H., et al. (2024). Aplp1 interacts with Lag3 to facilitate transmission of pathologic {alpha}-synuclein. Nature Communications, 15, 4663. https://doi.org/10.1038/s414scaling application:
1. In-vitro studies on Aplp1 and Lag3 interaction and their role in {alpha}-synuclein transmission in cell lines;
2. In-vivo studies using mouse models to investigate the effects of Apl1 and Lag3 deletion on {alpha}-synuclein pathology and neurodegeneration;
3. Behavioral tests to assess the therapeutic potential of anti-Lag3 antibody in treating {alpha}-synuclein-associated neurodegeneration;
4. NMR spectroscopy and co-immunoprecipitation experiments to analyze the structural basis for the interaction between Aplp1 and Lag3 and their binding to {alpha}-synuclein.
The study proposes that the Aplp1-Lag3 interaction is a potential therapeutic target for {alpha}-synucleinopathies such as Parkinson's disease.