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2 Acta Neurobiologiae Experimentalis

2 2011

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Cellular stress, nucleolar damage and neurodegeneration

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Parlato R.

nr S

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.

The influence of conditional inactivation of GR in noradrenergic system on stress related behavior in mice

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Kreiner G. , Chmielarz P. , Kusmierczyk J. , Parlato R. , Schuetz G. , Nalepa I.

nr S

Depression is a mental disease affecting complex cognitive and emotional functions. Stress induced hyperactivity of hypothalamic-pituitary-adrenal system (HPA) is believed to be one of the major contributors to its pathology. The activity of HPA is controlled by glucocorticoid receptors (GR) which function may be impaired in depression, resulting in reduced GR-mediated negative feedback on the HPA-axis. Most of the compounds which modulate GR action also influence noradrenergic system by increasing noradreneline levels. The aim of this study was to investigate if conditional inactivation of GR in noradrenergic neurons of mice affects the animal behavior in stressful conditions. Selective ablation of GR in noradrenergic system was achieved using the Cre/loxP approach by crossing transgenic mice hosting the Cre recombinase under the dopamine beta-hydroxylase (DBH) promoter with animals harboring the floxed GR gene. Resulting GRDBHCre mutant mice were born at expected rates, viable and showed no obvious physical impairment regarding life span, weight gain and locomotor activity. Also plasma cortisol levels did not differ between mutant and control mice. Animals were screened for anxiety and depressive-like behavior in light/ dark box test (LDT) and tail suspension test (TST). Male mutant mice did not unveil any differences from their control littermates in basal state nor after acute restraint stress (2 hrs). However, both tests performed after chronic restraint stress (14 days, 2 hrs/day) revealed that GRDBHCre mice were resistant to this type of experimental procedure showing similar anxiety status and immobility time as non-stressed controls. Our mutant mice may represent an interesting tool to study the role of stress in depression in context of noradrenergic system which is important target for antidepressant therapy. This study was supported by grant POIG.01.01.02-12-004/09 (DeMeTer) financed by European Regional Development Fund.