March 1, 2025
Uncategorized

Neuronal accumulation and spread of pathological α-synuclein (α-syn) fibrils are key events in Parkinson’s disease (PD) pathophysiology. However, the neuronal mechanisms underlying the uptake of α-syn fibrils remain unclear. In this work, we identified FAM171A2 as a PD risk gene that affects α-syn aggregation. Overexpressing FAM171A2 promotes α-syn fibril endocytosis and exacerbates the spread and neurotoxicity of α-syn pathology. Neuronal-specific knockdown of FAM171A2 expression shows protective effects. Mechanistically, the FAM171A2 extracellular domain 1 interacts with the α-syn C terminus through electrostatic forces, with >1000 times more selective for fibrils. Furthermore, we identified bemcentinib as an effective blocker of FAM171A2-α-syn fibril interaction with an in vitro binding assay, in cellular models, and in mice. Our findings identified FAM171A2 as a potential receptor for the neuronal uptake of α-syn fibrils and, thus, as a therapeutic target against PD.

Ever wondered how Parkinson’s disease spreads within the brain? Researchers are constantly working to understand this complex process, and a recent study has shed some light on a crucial piece of the puzzle: a gene called FAM171A2. It turns out this gene might play a significant role in how a harmful protein, alpha-synuclein (α-syn), accumulates and contributes to the progression of Parkinson’s.

Let’s break down this complex topic into easier-to-understand parts. You see, in Parkinson’s disease, α-syn clumps together, forming harmful “fibrils.” These fibrils spread from neuron to neuron, kind of like a domino effect, causing damage along the way. This study discovered that FAM171A2 might act as a doorway, making it easier for these harmful fibrils to enter brain cells.

Think of it like this: imagine each brain cell as a house. α-syn fibrils are like unwanted guests trying to get in. FAM171A2 is like a door that’s been left ajar, allowing these troublesome guests easy access. Once inside, they wreak havoc.

Here’s a summary of the key findings:

  • FAM171A2 identified as a Parkinson’s risk gene: Variations in this gene could make some individuals more susceptible to developing Parkinson’s.
  • FAM171A2 promotes α-syn uptake: The study found that higher levels of FAM171A2 lead to increased absorption of α-syn fibrils into neurons.
  • Knockdown of FAM171A2 is protective: When the researchers reduced the amount of FAM171A2, it protected neurons from the damaging effects of α-syn.
  • How it works: The FAM171A2 protein interacts with the α-syn fibrils, facilitating their entry into neurons. This interaction is highly specific to the fibril form of α-syn, meaning it’s much more attracted to the harmful clumps than to the normal form of the protein. They interact through electrostatic forces, kind of like magnets attracting each other.
  • A potential treatment? Researchers identified a drug called bemcentinib that can block the interaction between FAM171A2 and α-syn fibrils. This is a significant step, as it suggests a potential avenue for developing new therapies to slow or even halt the progression of Parkinson’s disease.

This research is truly exciting because it not only identifies a new player in Parkinson’s disease but also suggests a possible way to target it therapeutically. Bemcentinib’s ability to block the interaction between FAM171A2 and α-syn fibrils opens up a whole new world of possibilities for developing treatments. Imagine a drug that could effectively shut the “door” on these harmful fibrils, preventing them from spreading and causing further damage. While further research is needed, this study offers a glimmer of hope for those affected by this debilitating disease. It’s a crucial step towards understanding the complex mechanisms of Parkinson’s and developing effective therapies to combat it.