Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons

Abstract

Decreased rRNA synthesis and nucleolar disruption, known as nucleolar stress, are primary signs of cellular stress associated with aging and neurodegenerative disorders. Silencing of rDNA occurs during early stages of Alzheimer's disease (AD) and may play a role in dementia. Moreover, aberrant regulation of the protein synthesis machinery is present in the brain of suicide victims and implicates the epigenetic modulation of rRNA. Recently, we developed unique mouse models characterized by nucleolar stress in neurons. We inhibited RNA polymerase I by genetic ablation of the basal transcription factor TIF-IA in adult hippocampal neurons. Nucleolar stress resulted in progressive neurodegeneration, although with a differential vulnerability within the CA1, CA3, and dentate gyrus (DG). Here, we investigate the consequences of nucleolar stress on learning and memory. The mutant mice show normal performance in the Morris water maze and in other behavioral tests, suggesting the activation of adaptive mechanisms. In fact, we observe a significantly enhanced learning and re-learning corresponding to the initial inhibition of rRNA transcription. This phenomenon is accompanied by aberrant synaptic plasticity. By the analysis of nucleolar function and integrity, we find that the synthesis of rRNA is later restored. Gene expression profiling shows that 36 transcripts are differentially expressed in comparison to the control group in absence of neurodegeneration. Additionally, we observe a significant enrichment of the putative serum response factor (SRF) binding sites in the promoters of the genes with changed expression, indicating potential adaptive mechanisms mediated by the mitogen-activated protein kinase pathway. In the DG a neurogenetic response might compensate the initial molecular deficits. These results underscore the role of nucleolar stress in neuronal homeostasis and open a new ground for therapeutic strategies aiming at preserving neuronal function.

Altered Machinery of Protein Synthesis in Alzheimer's: From the Nucleolus to the Ribosome

“…UBF encoded by UBTF (upstream binding transcription factor, RNA polymerase I gene) is associated with NOR and is required for rDNA transcription by RNA polymerase 1 (83). It is known that altered expression of nucleolar chaperones and factors involved in rRNA synthesis results in nucleolar stress which in turn leads to impaired ribosomal biogenesis (4,58,69,79). The present observations show nucleolar stress in the hippocampus, mainly in CA1 but also in DG, in AD.…”

TIF-IA: An oncogenic target of pre-ribosomal RNA synthesis

“…In addition, it promotes p53-mediated apoptosis [74]. The depletion of TIF-IA in adult hippocampal neurons, however, has no impact on the survival of neural cells [75]. Hence, apoptosis induced by TIF-IA depletion is cell-type dependent.…”

A genetic mouse model for progressive ablation and regeneration of insulin producing beta-cells

“…28 Targeted deletion of TIF-IA in adult mouse hippocampus neurons induces a protracted neuronal degeneration, whereas in embryonic neural progenitors, it triggers a rapid apoptosis. 29,30 These observations suggested that the conditional ablation of TIF-IA could be used as a genetic tool to induce a protracted suicide response in slowly dividing or post-mitotic cells. Here, we report the development of a novel inducible b-cell loss model, based on the conditional ablation of TIF-IA, in which b-cell death occurs gradually and over a longer period of time compared to previously used animal models.…”