Fight Aging!

In mice, loss of Bubr1 produces high levels of DNA damage, cancer, and the appearance of accelerated aging. The proteins produced by this gene are an important part of the mechanisms controlling cell division, and their absence results in all sorts of harm to chromosomal structures. As is true of many such progeroid mechanisms related to DNA damage, it remains an open question as to whether Bubr1 is also relevant in normal aging. Interestingly, the production of artificially increased levels of Bubr1 in mice does modestly slow some measures of aging - but the effects on life span may be due to a reduction in cancer incidence rather than any other effect on the processes of aging. It is much harder than you might think to peel apart the various influences and causes in studies of this nature. One of the areas of focus in the study of Bubr1 and aging is the brain and its loss of function, particularly the declining rate at which new neurons are created; here is a short overview of recent research on this topic.

The hippocampus is one neurogenic region in the adult mammalian brain that continues to produce neurons well into adulthood. This process of neurogenesis occurs in the subgranular zone (SGZ) of the hippocampal dentate gyrus that harbors neural stem cells (NSCs). These actively participate in a sequential process where they proliferate, migrate and mature into neurons that are functionally integrated into the hippocampal circuitry. This is a highly plastic process that affords the hippocampus roles in memory formation, learning, and mood regulation. However, it is also an age-dependent one where the number of NSCs decline with age. Age-related cognitive disability is one example of the functional implications of deficits in this process. A molecular understanding of this course has so far eluded the field. Recent evidence has demonstrated that BubR1, a mitotic checkpoint kinase, decreases with natural aging and induces progeroid features and aging-related central nervous system (CNS) abnormalities. In our recent study we sought to address if BubR1 played a role in age-related hippocampal changes.

In this study, we show BubR1 is expressed in the radial-glia like NSCs (RGC), and its expression is reduced in an age-dependent manner. We used progeroid BubR1H/H mice with reduced hippocampal BubR1 levels to show significantly reduced proliferation. Progenitor cell types vulnerable to BubR1 insufficiency included significant reductions in activated RGCs, intermediate progenitor cells, and neuroblasts. Such changes in cellular proliferation were exacerbated in BubR1 H/H mice in an age-dependent manner. Next, we sought to address if BubR1 played a role in maturation of the surviving neurons. An in vitro analysis using post-mitotic neurons derived from adult NSCs showed BubR1 localization in the dendrites and the cytoplasm. BubR1H/H mice showed a significant increase in the portion of immature neurons with a concurrent decrease in mature neurons, indicating delayed neuronal maturation in BubR1H/H mice. Importantly, these morphological alterations were significantly rescued in BubR1-overexpression mice, suggesting a critical post-mitotic role of BubR1 in newborn neurons.

This study expands on the varied and emerging functions of BubR1 and implicates it as a key regulator in the age-dependent changes in adult hippocampal neurogenesis. In addition, while BubR1 is primarily known as a key component for mitosis, our study is the first to delineate the critical post-mitotic role for BubR1 in neuronal maturation. However, this study does not yet provide the mechanistic link or elucidation of the molecular machinery that occurs between BubR1 decrease and significant reductions in proliferation and maturation of newborn hippocampal neurons. Recent studies from our lab have identified involvement of Wnt signaling as a novel molecular regulator to this process. Furthermore, it remains to be understood if sustained BubR1 levels during aging process may have a protective role in the aged brain, and thus represent a novel therapeutic target for age-related cognitive declines. This is a future direction that can shed further light on BubR1 and aging.

Link: https://doi.org/10.18632/aging.101300