Periodic Reporting for period 5 - EAGER (Elucidating the effects of ageing on the nucleoporin-directed neural cell type-specific nuclear architecture and gene regulation)
Reporting period: 2024-04-01 to 2024-12-31
Ageing is one of the most critical risk factors for neurological and psychiatric diseases in developed countries. However, the biological links between brain ageing and age-related diseases remain largely unknown. Gaining a solid understanding of the cellular biology of neural ageing is essential for developing effective treatments for these conditions. Since neurons in the brain are mostly generated during development and have a very limited capacity for replacement or renewal, they must maintain their identity and function throughout our lives.
This project aims to investigate the biological connection between the fundamental mechanisms that support the long-term maintenance of neural identity and the effects of ageing on these processes. If successful, it could help us understand why ageing contributes to neurodegenerative diseases, explain why sporadic cases often manifest with stereotypical phenotypes, and identify potential common targets for initiating similar pathological processes. With this knowledge, we may be able to develop new strategies for diagnosis and treatment.
From this perspective, we focused on long-lived cellular components in the brain. While most proteins are replaced within a day to maintain cellular homeostasis, some are not replaced. These stable cellular components are likely crucial for supporting cellular function robustly, but they can accumulate damage over time. Previous studies have identified several long-lived proteins in the brain, yet their roles in brain maintenance and ageing remain poorly understood. Therefore, this project aims to investigate their physiological functions. Understanding their physiological function will reveal how and to what extent the age-dependent dysfunction of long-lived proteins leads to age-related brain malfunction and whether this contributes to the pathogenesis of age-related diseases. This is the first step in combatting sporadic age-related neurodegenerative diseases.
This project aims to investigate the biological connection between the fundamental mechanisms that support the long-term maintenance of neural identity and the effects of ageing on these processes. If successful, it could help us understand why ageing contributes to neurodegenerative diseases, explain why sporadic cases often manifest with stereotypical phenotypes, and identify potential common targets for initiating similar pathological processes. With this knowledge, we may be able to develop new strategies for diagnosis and treatment.
From this perspective, we focused on long-lived cellular components in the brain. While most proteins are replaced within a day to maintain cellular homeostasis, some are not replaced. These stable cellular components are likely crucial for supporting cellular function robustly, but they can accumulate damage over time. Previous studies have identified several long-lived proteins in the brain, yet their roles in brain maintenance and ageing remain poorly understood. Therefore, this project aims to investigate their physiological functions. Understanding their physiological function will reveal how and to what extent the age-dependent dysfunction of long-lived proteins leads to age-related brain malfunction and whether this contributes to the pathogenesis of age-related diseases. This is the first step in combatting sporadic age-related neurodegenerative diseases.
To address this question, we have investigated the role of nuclear pore proteins (Nups). Some Nups are long-lived proteins that constitute the stable nuclear pore complex, which organizes nuclear transport and also plays roles in epigenetic regulation. These long-lived proteins likely serve as stable platforms for cell type-specific gene regulation, but due to their extended half-life, they are also susceptible to damage during aging. Our ongoing research identified one of the Nups, Nup153, plays a critical role in the regulation neuronal gene expression and brain function.
Given the critical roles of Nup153 in brain function, we also explored Nup153-interacting proteins and identified lamin B1 as a regulator of adult neural stem cell (ANSC) aging. Lamin B1 is a nuclear lamin protein essential for maintaining nuclear membrane integrity and is also a long-lived protein. We found that lamin B1 is highly expressed in ANSCs within the hippocampus. Since ANSCs give rise to new neurons throughout life, this ongoing neurogenesis provides structural and functional plasticity to the adult hippocampus. However, lamin B1 levels in ANSCs decline with age, and premature reduction of lamin B1 in these cells leads to decreased neurogenesis and age-related mood dysregulation (published in EMBOJ, 2021). These findings suggest that both Nups and lamins are pivotal in maintaining brain plasticity, and the decline of these long-lived proteins may be a biological link to the initiation of age-dependent pathology. Intriguingly, lamin B1 expression patterns differ between mammals and anamniotes in the adult neurogenic regions, suggesting that lamin B1 may also contribute to the varying degrees of brain plasticity observed across evolution (published in Dev. Dyn 2025).
In parallel, beyond the roles of long-lived proteins, we sought other long-lived cellular components that could contribute to brain maintenance and aging. Although RNA is traditionally considered an unstable molecule, some evidence suggests that it can be retained for over a year in certain cell types, such as oocytes and plant seeds, which are both non-proliferating (quiescent) cells. As most brain cells, including neurons and ANSCs, are non-proliferating (post-mitotic or quiescent), we examined RNA turnover rates in the rodent brain. Strikingly, we discovered that some RNAs do not turn over for up to two years in certain brain cell types, including neurons and hippocampal ANSCs (published in Science, 2024). This finding challenges the current view of RNA stability and raises the possibility of unidentified roles for RNAs in brain ageing. While the functions of these long-lived RNAs remain unclear, our data suggest that they likely contribute to chromatin stability. These findings open up new avenues for research into brain ageing and RNA regulation.
Overall, our research has revealed the significant contributions of long-lived proteins and RNAs to neural plasticity and function. This has led to their identification as potential targets for addressing brain dysfunction associated with ageing.
Given the critical roles of Nup153 in brain function, we also explored Nup153-interacting proteins and identified lamin B1 as a regulator of adult neural stem cell (ANSC) aging. Lamin B1 is a nuclear lamin protein essential for maintaining nuclear membrane integrity and is also a long-lived protein. We found that lamin B1 is highly expressed in ANSCs within the hippocampus. Since ANSCs give rise to new neurons throughout life, this ongoing neurogenesis provides structural and functional plasticity to the adult hippocampus. However, lamin B1 levels in ANSCs decline with age, and premature reduction of lamin B1 in these cells leads to decreased neurogenesis and age-related mood dysregulation (published in EMBOJ, 2021). These findings suggest that both Nups and lamins are pivotal in maintaining brain plasticity, and the decline of these long-lived proteins may be a biological link to the initiation of age-dependent pathology. Intriguingly, lamin B1 expression patterns differ between mammals and anamniotes in the adult neurogenic regions, suggesting that lamin B1 may also contribute to the varying degrees of brain plasticity observed across evolution (published in Dev. Dyn 2025).
In parallel, beyond the roles of long-lived proteins, we sought other long-lived cellular components that could contribute to brain maintenance and aging. Although RNA is traditionally considered an unstable molecule, some evidence suggests that it can be retained for over a year in certain cell types, such as oocytes and plant seeds, which are both non-proliferating (quiescent) cells. As most brain cells, including neurons and ANSCs, are non-proliferating (post-mitotic or quiescent), we examined RNA turnover rates in the rodent brain. Strikingly, we discovered that some RNAs do not turn over for up to two years in certain brain cell types, including neurons and hippocampal ANSCs (published in Science, 2024). This finding challenges the current view of RNA stability and raises the possibility of unidentified roles for RNAs in brain ageing. While the functions of these long-lived RNAs remain unclear, our data suggest that they likely contribute to chromatin stability. These findings open up new avenues for research into brain ageing and RNA regulation.
Overall, our research has revealed the significant contributions of long-lived proteins and RNAs to neural plasticity and function. This has led to their identification as potential targets for addressing brain dysfunction associated with ageing.
We have identified the novel physiological roles of long-lived proteins in neuronal plasticity and their potential contribution to brain ageing. Furthermore, we have discovered how the regulation of long-lived proteins has diverged evolutionarily. These findings clearly exceed current knowledge. Additionally, we discovered long-lived RNAs in the brain that challenge current molecular biology dogma and open up completely new research avenues.