Neurodegenerative diseases like Alzheimer’s are marked by the accumulation of misfolded proteins that wreak havoc on neurons. One of the most notorious culprits is tau, a structural protein that, in its diseased form, clumps together into aggregates that spread throughout the brain. These aggregates interfere with normal cellular processes, leading to memory loss, behavioral changes, and other devastating symptoms. Preventing tau aggregation is therefore a key strategy for slowing the progression of these symptoms.
What if we could recruit molecular “helpers” to stop tau from accumulating?
A recent study published in Neuron explored this idea using a known protein domain that naturally localizes to tau aggregates: a short run of serines called polyserine. The researchers attached polyserine to a variety of proteins and found that this addition increased their enrichment at tau inclusions. For certain fusion proteins, such as TNPO3, VCP, and FAF2/UBXD8, the polyserine label also reduced the growth of tau aggregates.
To track protein recruitment and tau aggregation in living cells, the researchers relied on Promega’s HaloTag® Technology. By fusing HaloTag to FAF2 and other candidate proteins, and labeling them with Janelia Fluor® HaloTag® Ligands, they were able to visualize precisely how polyserine targeting drove localization to tau inclusions.
Among the candidates, FAF2, a known adaptor protein involved in protein quality control, proved the most effective. On its own, FAF2 offered some protection against tau accumulation. But when equipped with a polyserine tag, FAF2 became dramatically more effective, cutting tau aggregation by about 85% in cell models compared with only 50% for untagged FAF2. Notably, polyserine-tagged FAF2 lowered tau levels specifically in cells that already contained aggregates—precisely where it’s needed.
So how does FAF2 inhibit tau growth? The researchers uncovered two independent mechanisms. First, the UBA (ubiquitin-binding) and UBX (ubiquitin regulator) domains recognize ubiquitinated proteins and direct them toward proteasome-mediated degradation. Second, the membrane hairpin domain, which associates with the endoplasmic reticulum and lipid droplets, works through a separate proteasome-independent pathway. Importantly, FAF2 does not actively dismantle existing tau aggregates. Instead, it localizes to incoming tau seeds and prevents additional tau from accumulating on them—essentially reducing growth at the source.
The findings in cell-based assays were promising, but would they translate to living systems? In Drosophila, overexpressing FAF2 reduced a tau-induced eye degeneration phenotype, with the polyserine tag providing even stronger rescue. In tau-overexpressing transgenic mice, polyserine-tagged FAF2 lowered neuroinflammation and pathogenic tau levels. These mice also performed better in behavioral tests, showing reduced anxiety and improved contextual memory, suggesting a restoration of hippocampal function.
In summary, this study showed that polyserine-tagged FAF2 can inhibit tau aggregation in both cellular and animal models. It provides a proof of concept that polyserine targeting can be an effective strategy to inhibit tau growth and reduce neurodegenerative symptoms. Although more work is needed, these results mark an encouraging step toward new strategies that may one day reshape how we treat neurodegenerative disorders.
Reference: Van Alstyne, M. et al. (2025) Polyserine-Mediated Targeting of FAF2/UBXD8 Ameliorates Tau Aggregation. Neuron, in press. doi:10.1016/j.neuron.2025.08.002.
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