Aging significantly increases the risk of neurodegenerative disorders, yet the specific molecular processes involved remain elusive. A new study has investigated the role of PQBP3, a protein essential for maintaining the stability of the nuclear membrane, in the context of cellular aging and neurodegeneration. The results indicate that PQBP3 could serve as a promising target for therapy in addressing age-related neurodegenerative diseases.
As people age, the likelihood of developing neurodegenerative diseases like Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis rises. However, the reasons why these conditions become more common with age are still being explored. The molecular connections tying aging, cellular aging, and the emergence of these disorders are not fully understood.
In a recent publication dated August 5, 2024, in The EMBO Journal, researchers from Tokyo Medical and Dental University (TMDU) in Japan have revealed a significant advancement in understanding this issue by examining the function of a specific nucleolar protein.
The study, led by Professor Hitoshi Okazawa, revisited polyglutamine binding protein 3 (PQBP3), a protein they initially identified over two decades ago. By thoroughly screening normal proteins that interact with disease-related proteins in disorders linked to polyglutamine, such as Huntington’s disease, they pinpointed various proteins within the PQBP group. After investigating PQBP1 and PQBP5, Prof. Okazawa and his team pivoted their focus to PQBP3.
To investigate the significance of PQBP3, the team utilized cellular senescence as a platform for studying aging. Cellular senescence is characterized by cells that cease division but remain alive and metabolically active. This naturally occurring phase, observable in our bodies, often manifests in aging cells and can be simulated in laboratory settings.
Using advanced super-resolution fluorescence microscopy, the scientists made an interesting observation regarding PQBP3’s localization. “Typically, PQBP3 is found around the edges of the nucleolus within the nucleus, but during senescence, PQBP3 shifts from the nucleolus into the nucleoplasm or cytoplasm,” states Prof. Okazawa. He further notes, “This shift of PQBP3 corresponded with the leakage of nuclear DNA into the cytoplasm. Crucially, electron microscopy revealed that the structure of the nuclear membrane was destabilized in cells with cytoplasmic PQBP3.”
To better understand the destabilization of the nuclear membrane, the researchers performed a bioinformatics analysis utilizing protein interaction databases. Their findings indicated that PQBP3 interacts with a protein known as proteasome activator complex subunit 3, or PSME3, which is vital for protein degradation. Further studies revealed that normally, some PQBP3 moves from the nucleolus to the nuclear membrane, where it binds to PSME3 and inhibits the breakdown of Lamin B1, a protein integral to the nuclear membrane’s integrity. However, in senescent cells, this process diminishes, leading to accelerated degradation of Lamin B1 and subsequent destabilization of the nuclear membrane.
To connect these conclusions to neurodegenerative diseases, the team conducted experiments with cell cultures and mouse models of spinocerebellar ataxia type 1 (SCA1), a polyglutamine disorder. They discovered that PQBP3 was affected by inclusion bodies—abnormal protein aggregates typical of SCA1. This reduced the levels of PQBP3 in the nucleolus, impairing its functions and resulting in membrane destabilization.
Overall, the study provides insight into a potential shared factor between aging and neurodegenerative disorders. The new understanding of PQBP3 positions it as a potential target for innovative therapeutic approaches. As Prof. Okazawa observes, “Loss of PQBP3 function can occur in both cellular aging and neurodegeneration in brain neurons. Therefore, theoretically targeting PQBP3 could enhance both brain aging and neurodegeneration.” However, he cautions that in non-neuronal cells, PQBP3 may pose a cancer risk, as cellular aging can help suppress cancer development. “PQBP3 might serve as a double-edged sword, involved in fundamentally different biological issues like cancer and neurodegeneration,” he warns.
In conclusion, clarifying the connections between aging and neurodegeneration could lead to innovative and effective treatments for these conditions.
