Almeida, A. | bioRxiv Science

bioRxiv2018

Amyloid-β promotes neurotoxicity by Cdk5-induced p53 stabilization

The p53 tumor suppressor protein, a key regulator of cell apoptosis, has been described to accumulate in affected brain areas from Alzheimers disease (AD) patients. However, whether p53 plays any role in AD pathogenesis remains unknown. Here, we found that exposure of neurons to oligomers of the amyloidogenic fragment 25-35 of the A{beta} peptide (A{beta}25-35) activated Cdk5, which promoted p53 protein phosphorylation and stabilization. Moreover, A{beta}25-35-mediated mitochondrial dysfunction and neuronal apoptosis were prevented by both genetic and pharmacological inhibition of either p53 or Cdk5 activities. To confirm this mechanism in vivo, A{beta}25-35 was stereotaxically injected in the cerebral right ventricle of mice, a treatment that caused p53 protein accumulation, dendrite disruption and neuronal death. Furthermore, these effects were prevented in p53 knockout mice or by pharmacologically inhibiting p53. Thus, A{beta}25-35 triggers Cdk5 activation to induce p53 phosphorylation and stabilization, which leads to neuronal damage. Inhibition of the Cdk5-p53 pathway may therefore represent a novel therapeutic strategy against A{beta}-induced neurodegeneration.

neuroscience↗

bioRxiv2018

Chromosome (mis)segregation is biased by kinetochore size

Summary:\n\nAneuploidy, the gain or loss of chromosomes, arises through problems in chromosome segregation during mitosis or meiosis and has been implicated in cancer and developmental abnormalities in humans [1]. Possible routes to aneuploidy include a compromised spindle assembly checkpoint (SAC), cohesion defects, centrosome amplification, as well as improper kinetochore-microtubule attachments [2]. However, none of these established routes takes into account the intrinsic features of the kinetochore - the critical chromosomal interface with spindle microtubules. Kinetochore size and respective microtubule binding capacity varies between different animal and plant species [3-10], among different chromosomes from the same species (including humans) [3, 11-15], and in response to microtubule attachments throughout mitosis [16-18]. How kinetochore size impacts chromosome segregation remains unknown. Addressing this fundamental question in human cells is virtually impossible, because most of the 23 pairs of chromosomes cannot be morphologically distinguished, while detection of 2-3 fold differences in kinetochore size is limited by diffraction and cannot be resolved by conventional light microscopy in living cells. Here we used the unique cytological attributes of female Indian muntjac, the mammal with the lowest known chromosome number (n=3), to track individual chromosomes with distinct kinetochore sizes throughout mitosis. We found that chromosomes with larger kinetochores bi-orient more easily and are biased to congress to the equator in a motor-independent manner. However, they are also more prone to establish erroneous merotelic attachments and lag behind during anaphase. Thus, we uncovered an intrinsic kinetochore feature - size - as an important determinant of chromosome segregation fidelity.

cell biology↗