Multitasking by the neuronal nucleolus: stress sensing and neurotrophic responses
The ribosome is the nexus for all cellular protein translation. Critical steps of ribosomal biogenesis occur in the nucleolus, which is a nuclear subdomain that contains tandem repeats of nucleolar rRNA genes (rDNA). Ribosomal biogenesis is initiated by the RNA-Polymerase-1 (Pol1)-mediated transcription of those genes. That process is a primary site for the regulatory inputs adjusting ribosomal production to cellular needs. Although prominent nucleolar presence has been noted in neurons nearly 200 years ago, studies that directly address significance of that structure for neuronal development and/or homeostasis started to appear only recently. Our recent work has demonstrated that Pol1 serves as a sensor of neuronal DNA damage. Thus, DNA single strand breaks and/or DNA-protein adducts but not DNA double strand breaks inhibit Pol1 leading to disruption of nucleolar structure. Unlike developmentally-restricted apoptosis, such a nuclear stress response also occurs in adult neurons that are challenged with DNA damage. In developing neurons, nucleolar stress leads to activation of p53 and the p53-dependent apoptosis. Conversely, during normal development, Pol1 is major transcriptional effector for neurite outgrowth. The pro-neuritic neurotrophin BDNF increases Pol1-mediated transcription in an ERK1/2-dependent manner while Pol1 is both necessary and sufficient for the BDNF/ ERK1/2-stimulated neurite outgrowth. Finally, studies of human cerebro-cortical samples from 33 Alzheimer’s disease (AD) patients and 24 age-matched controls reveal AD-associated epigenetic silencing of rDNA as rDNA promoter becomes hypermethylated. Such a change in the epigenetic landscape of the AD cortical genome appears reducing ribosomal biogenesis and stabilizing rDNA.
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