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Researchers have identified two molecules whose interaction significantly increases the spread of the toxic alpha-synuclein protein in neurons, a key feature of Parkinson’s disease. Targeting one of them with an FDA-approved anticancer drug would inhibit this interaction, leading to a significant reduction in the amount of the alpha-synuclein protein. The drug could thus constitute a promising option for slowing the progression of the disease.
Affecting nearly 8.5 million people worldwide, Parkinson’s is the second most common neurodegenerative disease, after Alzheimer’s. It manifests itself by progressive movement disorders (tremors, stiffness, balance problems, speech difficulties, etc.) as well as mood and cognitive function disorders. These symptoms are due to the excessive accumulation of misfolded alpha-synuclein proteins in neurons and glial cells.
While soluble alpha-synuclein is essential for synaptic communication, misfolded alpha-synuclein is a toxic form that gradually spreads from the enteric and peripheral nervous systems to the central nervous system. Its accumulation induces a form of programmed death (a process called “parthanatos”) of dopaminergic neurons, which results in the typical symptoms of the disease.
The spread of pathological alpha-synuclein is therefore considered to be an essential mechanism for the pathogenicity of the disease. This process occurs through cell surface receptors mediating both its propagation between neurons and its uptake by them. Among these receptors is, for example, the lymphocyte activation gene 3 (Lag3).
Previous studies have shown that its deletion significantly reduces the uptake of toxic alpha-synuclein by neurons, without stopping it. This suggests that other receptors may be partially involved in the spreading and uptake of the protein.
The team in the new study suggests that it could be the beta-amyloid precursor protein type 1 (Aplp1). Indeed, it has notably been shown that this protein binds specifically to pathological alpha-synuclein and is associated with neurodegeneration. However, its involvement in the propagation of alpha-synuclein was previously unexplored.
« Our work previously demonstrated that Lag3 is not the only cell surface protein that helps neurons take up alpha-synuclein. We therefore turned to Aplp1 in our more recent experiments », Explains in a press release the co-lead author of the new study, Valina Dawson, of Johns Hopkins University (in the United States). Researchers from Nagaoka University of Technology (Japan), University of Heidelberg (Germany), University of Pittsburgh and the Chinese Academy of Sciences also participated in the study.
Overview of neurons expressing Aplp1 (white), a key protein that allows brain cells to take up alpha-synuclein, which causes Parkinson’s disease. © Yasuyoshi Kimura
A 90% reduction in absorption of toxic proteins
To support their hypothesis, the researchers selected transgenic mice lacking either Aplp1 or Lag3, or both. They found that deletion of Aplp1 significantly reduced the uptake of toxic alpha-synuclein and its neuron-to-neuron transmission. Behavioral deficits were also reduced in mice lacking the receptor. A similar effect was observed in mice lacking Lag3.
However, the effect was even greater in mice lacking both receptors. Cellular uptake of the harmful protein alpha-synuclein dropped by 90%, while loss of dopamine neurons and behavioral deficits were almost non-existent. This suggests that the interaction between the two proteins plays a key role in disease progression. The binding of Aplp1 with Lag3 on the surface of neurons would allow them to massively absorb toxic alpha-synuclein circulating in the intercellular space, which would lead to parthanatos.
Aplp1 and Lag3 interact with each other. (a) Lag3 inhibits Aplp1 by anti-Lag3 410C9 immunoprecipitation in WT mouse brain lysates, but not in Lag3–/– lysates. (b) Aplp1 inhibits Lag3 by anti-Aplp1 CT11 immunoprecipitation in WT mouse brain lysates, but not in Aplp1–/– lysates. (c, d) Mapping of Lag3-binding domains in Aplp1. (e) Mapping of Aplp1-binding domains in Lag3. The experiments in (a–e) were repeated three times independently with similar results. (f–h) Identification of the interface of A1E1 (E1 domain of APLP1) binding to L3D2 (D2 domain of LAG3). © Xiaobo Mao et al.
A drug that could target a range of neurodegenerative diseases
The researchers deduced that this interaction could be a potentially promising target for treating the disease. Nivolumab/relatlimab, an anti-Lag3 antibody approved in 2022 by the FDA for the treatment of melanoma, could inhibit this interaction.
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By injecting the drug into mice that were not genetically modified (i.e., provided with Aplp1 and Lag3 receptors), the drug effectively inhibited the spread and uptake of misfolded alpha-synuclein. This effect was further greater than that of genetic deletion of Lag3, due to the close association between the two receptors.
These results suggest that the drug could be used both as a treatment for Parkinson’s and for other neurodegenerative diseases involving the Aplp1 receptor, such as Alzheimer’s. “ Our results suggest that targeting this interaction with drugs could significantly slow the progression of Parkinson’s disease and other neurodegenerative diseases “, says study co-author Xiaobo Mao, also of Johns Hopkins University.
On the other hand, given that Alzheimer’s is also characterized by the interaction of the tau protein with the Lag3 receptor, it would logically be possible to treat it with the same anti-Lag3 antibody. As a next step, the researchers plan to evaluate the effectiveness of nivolumab/relatlimab in mouse models of the two pathologies. The results of the study are published in the journal Nature Communications.
Source : Nature Communications
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