Cellular stress, nucleolar damage and neurodegeneration
The nucleolus regulates its activity in favorable or adverse conditions to optimize the cellular resources. Decreased rRNA synthesis is associated with aging and is present in age-related neurodegenerative disorders. Among the causes of neuronal death, reduced neurotrophic support and increased oxidative stress lead to down-regulation of rRNA synthesis and consequent nucleolar disruption (“nucleolar stress”) making this organelle a critical sensor and mediator of the cellular stress response. Inhibition of rRNA synthesis leads to a condition of chronic stress by the stabilization of the tumor suppressor p53. p53 is a convergence point in the molecular pathways leading to different neurodegenerative diseases. However, depending on the stress signals p53 induces a variety of responses (e.g., cell-cycle arrest, senescence, apoptosis) with protective and detrimental effects. For therapeutic interventions identifying the elements that define a particular p53-mediated outcome remains a central question. To explore the impact of nucleolar stress on selective neuronal survival, we developed genetically modified mice in which the transcription factor TIFIA, essential for rRNA synthesis, is ablated in specific neuronalpopulations by the Cre-loxP system. Inhibition of rRNA synthesis and nucleolar disruption in either dopaminergic neurons or medium spiny neurons of the striatum leads to severe oxidative damage, progressive neuronal loss and typical motor dysfunctions. Gene expression profiling and biochemical assays accompanied with electron microscopy analysis, reveal the downregulation of the PI3K/mTOR signaling and activation of neuroprotective responses, such autophagy, prior to cell death. These analyses highlight the role of the nucleolus as mediator of the stress response during neurodegeneration and provide mechanistic insights into the modes of action of p53 in the neuronal-specific responses to chronic stress.
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