Cancer Drug Shows Promise in Blocking Parkinson's Disease Spread in Preclinical Study
核心洞察
Researchers identified Aplp1 (搜索), a cell surface protein, as a key player in the spread of alpha-synuclein (搜索), a protein implicated in Parkinson's disease (搜索).
An FDA-approved cancer drug targeting Lag3 (搜索), which interacts with Aplp1 (搜索), effectively blocked the spread of alpha-synuclein (搜索) clumps in mouse models.
The anti-Lag3 (搜索) antibody demonstrated superior efficacy compared to Lag3 depletion, preventing further spread of alpha-synuclein (搜索) seeds.
Researchers at Johns Hopkins University have identified a novel mechanism for the spread of Parkinson's disease (搜索) and demonstrated that an FDA-approved cancer drug can effectively block this process in preclinical models. The study, published in Nature Communications, reveals that the cell surface protein Aplp1 (搜索) plays a crucial role in the transmission of misfolded alpha-synuclein (搜索), a hallmark of Parkinson's disease, between brain cells. This discovery has led to the finding that a cancer drug targeting Lag3 (搜索), a protein that interacts with Aplp1, can halt the spread of the disease in mice.
Aplp1's Role in Alpha-Synuclein Spread
Parkinson's disease (搜索), the second most common neurodegenerative disorder affecting over 8.5 million people worldwide, is characterized by the accumulation of misfolded alpha-synuclein (搜索) in Lewy bodies within neurons. This accumulation leads to the death of dopamine-producing neurons in the substantia nigra, resulting in motor and cognitive impairments. While the exact cause of Parkinson's is unknown, the spread of misfolded alpha-synuclein between cells is believed to be a key factor in disease progression.
Previous research has shown that Lag3 (搜索) binds to alpha-synuclein (搜索) and facilitates its spread. However, deleting Lag3 only partially impedes the spread, suggesting the involvement of other proteins. Valina Dawson, a neuroscientist at Johns Hopkins, explained, "Our work previously demonstrated that Lag3 wasn't the only cell surface protein that helped neurons absorb alpha-synuclein, so we turned to Aplp1 (搜索) in our most recent experiments."
Blocking Aplp1-Lag3 Interaction
Experiments with genetically modified mice revealed that Aplp1 (搜索) and Lag3 (搜索) independently assist brain cells in absorbing alpha-synuclein (搜索), but together, they significantly enhance the uptake. Mice lacking both Aplp1 and Lag3 exhibited a 90% reduction in alpha-synuclein absorption compared to those missing only one protein.
Further experiments involved administering nivolumab/relatlimab, a melanoma (搜索) medication containing a Lag3 (搜索) antibody, to mice. The researchers found that this drug effectively blocked the interaction between Aplp1 (搜索) and Lag3, nearly eliminating the formation of alpha-synuclein (搜索) clumps in neurons. Ted Dawson, another Johns Hopkins neuroscientist, noted, "The anti-Lag3 antibody was successful in preventing further spread of alpha-synuclein seeds in the mouse models and exhibited better efficacy than Lag3-depletion because of Aplp1's close association with Lag3."
Implications for Parkinson's Treatment
These findings suggest that targeting the Aplp1 (搜索)-Lag3 (搜索) interaction could be a promising therapeutic strategy for Parkinson's disease (搜索). Xiaobo Mao from Johns Hopkins University stated, "Now that we know how Aplp1 and Lag3 interact, we have a new way of understanding how alpha-synuclein (搜索) contributes to the disease progression of Parkinson's disease. Our findings also suggest that targeting this interaction with drugs could significantly slow the progression of Parkinson's disease and other neurodegenerative diseases."
The research team plans to further investigate the effects of Lag3 (搜索) antibodies in mouse models of Parkinson's and Alzheimer's disease (搜索). This work could pave the way for the development of novel therapies to prevent or slow the progression of these debilitating neurodegenerative conditions.