Aging is the leading cause of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. But what exactly increases the prevalence of these brain disorders as one ages? The molecular forces that link aging, cellular senescence, and the onset of these neurodegenerative disorders are not yet well understood.
In a recent study published online on August 5, 2024 in The EMBO journalresearchers from Tokyo Medical and Dental University (TMDU) in Japan have uncovered a crucial piece of this puzzle by focusing on the role of a single nucleolar protein.
A research team led by Professor Hitoshi Okazawa has revisited polyglutamine binding protein 3 (PQBP3), a protein they themselves discovered more than twenty years ago. Through extensive screening of normal proteins that bind to disease-causing proteins in polyglutamine diseases such as Huntington’s disease, they identified several proteins in the PQBP family. After investigating the functions and pathological relevance of PQBP1 and PQBP5, Prof. Okazawa and colleagues turned their attention to PQBP3.
To shed light on the role of this protein, the researchers used cellular aging as a model to study aging. Senescence refers to a state in which a cell no longer undergoes division, but remains alive and metabolically active. This condition, which can be replicated in cell cultures, occurs naturally in our bodies and is typically observed in aging cells.
Using super-resolution fluorescence microscopy observations, the researchers observed something peculiar about the location of PQBP3. “PQBP3 typically localizes around the periphery of the nucleolus in the nucleus, but during aging PQBP3 translocated from the nucleolus to the nucleoplasm or cytoplasm,” says Prof. Okazawa. He adds: “This translocation of PQBP3 was accompanied by leakage of nuclear DNA into the cytoplasm. Most importantly, we subsequently observed via electron microscopy that the nuclear membrane structure was destabilized in cells where PQBP3 had translocated to the cytoplasm.”
To shed light on this destabilization of the nuclear membrane, the researchers performed a bioinformatics analysis using protein interaction databases. The results suggested that PQBP3 binds to a protein called proteasome activator complex subunit 3, or PSME3, which plays a key role in the degradation of other proteins. Upon further investigation, the team found that, under normal conditions, some of PQBP3 moves from the nucleolus to the nuclear membrane and binds to PSME3, suppressing the breakdown of Lamin B1, another protein found in the nuclear membrane. However, the rate of these changes slows down in senescent cells and so Lamin B1 is broken down more quickly, failing to stabilize the nuclear membrane.
Finally, to link these findings to neurodegenerative disorders, the researchers conducted experiments in cell cultures and mouse models of spinocerebellar ataxia type 1 (SCA1), a polyglutamine disease. They found that PQBP3 was ‘captured’ by so-called inclusion bodies, which are abnormal protein aggregates characteristic of SCA1. This in turn reduced the levels of PQBP3 in the nucleolus, limiting its functionality and leading to the destabilization of the cell membrane.
Taken together, the results of this study shed light on a possible common aspect of aging and neurodegenerative diseases. This newfound understanding of PQBP3 makes it a potential target for new treatments, as Prof. Okazawa notes: “Since PQBP3 loss of function can occur in both cellular aging and neurodegeneration in brain neurons. Therefore, targeting PQBP3 theoretically makes it possible to improve both brain aging and neurodegeneration.” However, in cells other than neurons, PQBP3 may be a risk factor for cancer, as cellular senescence likely helps suppress cancer. “PQBP3 may be a double-edged sword as it is involved in a fundamental biological problem of contrasting cellular pathologies, namely cancer and neurodegeneration,” warns Prof. Okazawa.
In summary, unraveling the link between aging and neurodegeneration could pave the way for new and effective therapies for these diseases.
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Magazine reference:
Yoshioka, Y., et al. (2024). PQBP3 prevents aging by suppressing PSME3-mediated proteasomal Lamin B1 degradation. The EMBO journal. doi.org/10.1038/s44318-024-00192-4.