In studies with genetically engineered mice, Johns Hopkins Medicine researchers say they have identified a potentially new biological target involving APLP1, a cell surface protein that drives the spread of Parkinson’s disease-causing alpha-synuclein. The findings reveal how APLP1 connects with Lag3, another cell surface receptor, in a key part of a process that helps spread harmful alpha-synuclein proteins to brain cells. Those protein buildups are hallmarks of Parkinson’s disease. Long-standing studies have shown that by clumping together and forming protein deposits, misfolded alpha-synuclein proteins journey from brain cell to brain cell, killing those responsible for producing dopamine, and causing Parkinson’s disease to progress through a type of “programmed” cell death called parthanatos, leads to impairments in movement, emotional regulation and thinking.
The investigation was led by Xiaobo Mao and Ted Dawson, PhD, associate professors of Neurology at the Johns Hopkins University School of Medicine. APLP1’s bond with Lag3 on the cell’s surface enables healthy brain cells to absorb traveling clumps of alpha-synuclein, leading to cell death. In mouse studies published in 2016 and 2021, Mao and Dawson’s team identified Lag3’s role in binding with alpha-synuclein proteins, causing Parkinson’s disease to spread. However, those studies indicated that another protein was partially responsible for the cell’s absorption of misfolded (pathological) alpha-synuclein. They demonstrated that Lag3 wasn’t the only cell surface protein that helped neurons absorb alpha-synuclein, so they focused to APLP1. Notably, Lag3 is already the target of a combination cancer drug approved by the american FDA that uses antibodies to “teach” the human immune system what to seek and destroy.
To determine whether Aplp1 indeed contributed to the spread of harmful alpha-synuclein proteins, researchers used a line of genetically engineered mice lacking either APLP1 or Lag3 or both the receptors. In mice without APLP1 and Lag3, cell absorption of the harmful alpha-synuclein dropped by 90%. After injecting mice with the Lag3 antibody, they found that this drug also blocks the interaction of APLP1 and Lag3, meaning healthy brain cells could no longer absorb alpha-synuclein clumps. The researchers say the Lag3 antibody nivolumab/relatlimab, a drug approved in 2022 for cancer treatment, could play a role in preventing cells from absorbing alpha-synuclein. Effectively, 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.
This research has potential applications in treating other neurodegenerative conditions that have no cures, Mao says. In Alzheimer’s disease, which is associated with symptoms of memory loss, mood instability and muscle problems, tau proteins become misfolded and clump together in neurons at high levels, worsening the condition. In Alzheimer’s research, Mao says scientists could try to target Lag3 (which also binds with the dementia-related tau protein) with the same antibody. With the success of using the Lag3 antibody in mice, the Johns Hopkins scientists state the next steps would be to conduct anti-Lag3 antibody trials in mice with Parkinson’s disease and Alzheimer’s disease. They are also looking into how they could prevent unhealthy cells from releasing the pathological form of alpha-synuclein in the first place.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Mao X et al. Nat Commun. 2024 May 31; 15(1):4663.
Adv Sci (Weinh). 2023; 10(25):e2301903.
PNAS USA. 2021; 118(26):e2011196118.