A study published in The EMBO Journal by Nirbhik Acharya and Carlos Castañeda at Syracuse University's College of Arts & Sciences reveals new details about how cells clean up damaged proteins, with implications for neurodegenerative diseases. The findings were announced on Apr. 15 and focus on the mechanisms that may fail in conditions such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia.
The research matters because when a cell's protein cleanup system breaks down, damaged proteins accumulate, forming clumps linked to several neurodegenerative disorders. Understanding why this process fails could help identify new targets for therapies.
Castañeda's team studied Dsk2, a yeast protein similar to human ubiquilin-2, which helps transport damaged proteins to be recycled. Using nuclear magnetic resonance spectroscopy, they observed how Dsk2 changes shape under stress and forms temporary clusters called biomolecular condensates. These clusters allow the cell to gather and potentially process damaged proteins efficiently.
The researchers found that a specific part of Dsk2 called the STI1 domain acts like a clamp, allowing different segments of the protein—and even multiple molecules—to connect briefly into these clusters. Removing either Dsk2 or its key segments disrupted cluster formation and impaired protein quality control in cells.
The study combined efforts from four research teams who used computer simulations, cell-based experiments, and structural biology techniques such as X-ray crystallography. Parallel work led by Matthew Wohlever at the University of Pittsburgh revealed that mutations linked to ALS interfere with how the STI1 clamp operates in human ubiquilin proteins.
"We realized that we saw a similar molecular mechanism working in both yeast and human versions of ubiquilin," said Castañeda about their collaborative breakthrough. He added: "We're starting to understand the rules." Looking ahead, Castañeda suggested that learning how to intervene when these processes break down could offer common strategies for treating various neurodegenerative diseases.
