Scientists have uncovered a powerful ally in the fight against neurodegenerative diseases: a nucleolar complex that plays a pivotal role in maintaining cellular health through protein homeostasis (proteostasis), by which cells maintain the balance and proper functioning of their proteins. By suppressing this complex, researchers have shown it’s possible to dramatically reduce the toxic effects of Alzheimer’s-causing proteins, boosting the cell’s natural defenses through enhanced degradation of hazardous proteins. This mechanism regulates proteostasis across tissues by modulating TGF-β signaling, a pathway involved in cell growth, differentiation, and tissue homeostasis. This breakthrough opens exciting new possibilities for the development of new therapies that could slow or even prevent diseases like Alzheimer’s, offering hope for a future of healthy aging.
As we age, the intricate balance of protein homeostasis (proteostasis) — the system responsible for maintaining cellular health by ensuring proteins are correctly folded— begins to falter. This decline leads to the accumulation of toxic protein aggregates, a hallmark and an underlying cause of neurodegenerative diseases such as Alzheimer’s disease. A new study led by Hebrew University researchers Prof. Ehud Cohen and the student Huadong Zhu from the Department of Biochemistry and Molecular Biology at the Institute for Medical Research Israel–Canada (IMRIC) in collaboration with the lab of Dr. Yonatan Tzur of the Alexander Silberman institute of Life Science, sheds light on a promising new way to address this issue, with implications that extend far beyond basic research.
The research identifies that a nucleolar complex, FIB-1-NOL-56, is a central player in the regulation of proteostasis at the cellular and organismal levels. By suppressing the activity of this complex, the team observed a marked reduction in the toxic effects of Alzheimer’s-associated Aβ peptide and another disease-causing protein, in model organisms. This discovery not only deepens our understanding of how the body manages cellular stress but also offers hope for future treatments that could delay or prevent a myriad of devastating neurodegenerative diseases.
“Our findings go beyond the lab bench,” explains Prof. Cohen. “Neurodegenerative diseases affect millions of people worldwide, impacting families and caregivers. By uncovering how cells communicate to maintain protein integrity, we’re opening the door to the development of preventive therapeutic approaches that could delay disease onset and significantly improve quality of life of the elderly”.
This research has a real-world relevance that’s hard to ignore. Neurodegenerative diseases like Alzheimer’s disease touch nearly every family, affecting not just patients but also their loved ones. The ability to slow or prevent these conditions could mean more meaningful moments with aging parents, fewer health crises, and a longer period of independence for millions of older adults.
As the team looks ahead to translating these discoveries into treatments, the potential to improve the lives of countless individuals grows ever clearer. With continued research, this approach could lead to a future where aging does not come hand-in-hand with the specter of neurodegenerative disease.
The research paper titled “A nucleolar mechanism suppresses organismal proteostasis by modulating TGF-β/ERK signaling” is now available in Nature Cell Biology and can be accessed at https://doi.org/10.1038/s41556-024-01564-y.
Researchers:
Huadong Zhu1, Reut Bruck-Haimson1, Adam Zaretsky1, Irit Cohen1, Roni Falk2, Hanna Achache2, Yonatan B. Tzur2 and Ehud Cohen1
Institutions:
1) Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel – Canada (IMRIC). The Faculty of Medicine of the Hebrew University of Jerusalem
2) Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem
The Hebrew University of Jerusalem is Israel’s premier academic and research institution. With over 23,000 students from 90 countries, it is a hub for advancing scientific knowledge and holds a significant role in Israel’s civilian scientific research output, accounting for nearly 40% of it and has registered over 11,000 patents. The university’s faculty and alumni have earned eight Nobel Prizes, two Turing Awards and a Fields Medal, underscoring their contributions to ground-breaking discoveries. In the global arena, the Hebrew University ranks 81st according to the Shanghai Ranking. To learn more about the university’s academic programs, research initiatives, and achievements, visit the official website at http://new.huji.ac.il/en