I.The LCD as a "Sticky" Switch for Protein Aggregation

The 2025 Lasker Basic Medical Research Award highlights a paradigm shift in our understanding of neurodegenerative disease, recognizing foundational discoveries on low-complexity domains (LCDs)—intrinsically disordered protein regions now known to drive pathological phase transitions and protein aggregation in neurodegenerative disorders. 

The LCD in Galectin-3's N-terminal region is essentially a repetitive and flexible chain of amino acids. Unlike a protein's more rigid, structured domains, this region doesn't have a fixed shape. It's this lack of a defined structure that gives it its unique and dangerous function in neurodegenerative diseases.

This "stickiness" allows Galectin-3's LCD to promote protein aggregation in a couple of key ways:

Self-Association and Scaffolding: The LCDs of multiple Galectin-3 molecules can interact with each other. This allows Galectin-3 to form clusters, or oligomers. These clusters then act as a scaffold, or a kind of molecular glue. Other proteins prone to misfolding, like amyloid-beta in Alzheimer's or alpha-synuclein in Parkinson's, can then bind to this scaffold. This dramatically accelerates their aggregation into toxic plaques and tangles.

Liquid-Liquid Phase Separation (LLPS): The weak, repetitive interactions of the LCD are perfect for a process called liquid-liquid phase separation. Imagine oil and water separating; LLPS is a similar process inside and outside of cells. The LCD allows Galectin-3 to condense into dense, liquid-like droplets. Within these droplets, the concentration of both Galectin-3 and other amyloidogenic proteins becomes incredibly high. This crowded environment acts as an incubator, speeding up the formation of the insoluble protein aggregates that are a hallmark of many neurodegenerative diseases.

In short, the LCD's flexibility and repetitive nature allow it to initiate a chain reaction, bringing together molecules that would otherwise remain separate and soluble.

II. Connecting the Dots: LCD, Aggregation, and Neuroinflammation

The trouble doesn't stop with protein aggregation. Galectin-3's LCD is also a key player in driving chronic and damaging neuroinflammation. Here's how it connects the two:

Activating Microglia: The brain's immune cells, called microglia, recognize protein aggregates as a threat. When Galectin-3 promotes the formation of these aggregates, it essentially sounds the alarm for microglia to switch into an activated, pro-inflammatory state.

A Vicious Cycle: Once activated, microglia release more Galectin-3. This newly released Galectin-3, with its sticky LCD, then goes on to promote even more protein aggregation. This creates a destructive feedback loop where aggregation fuels inflammation, and inflammation, in turn, fuels more aggregation. This chronic inflammation is highly damaging to neurons and is a major contributor to the cognitive and motor decline seen in neurodegenerative diseases.

Direct Inflammatory Signaling: Beyond its role in aggregation, the clustering of Galectin-3 via its LCD can also directly trigger inflammatory pathways. By bringing together receptors on the surface of microglia, the clustered Galectin-3 can amplify pro-inflammatory signals, even in the absence of large protein aggregates.

In summary, the Low-Complexity Domain of Galectin-3 acts as a master regulator of a toxic cascade. Its inherent "stickiness" provides the initial scaffold for protein aggregation through processes like phase separation. This aggregation then triggers a chronic and self-perpetuating neuroinflammatory response, which is a key driver of neuronal damage and disease progression.