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1

Cellular stress, nucleolar damage and neurodegeneration

100%
Parlato R.
Acta Neurobiologiae Experimentalis
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2011
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tom 71
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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.
2

Disruption of nucleolar activity in dopaminergic neurons leads to progressive parkinsonism

51%
Schutz G., Parlato R., Rieker C., Kreiner G.
Acta Neurobiologiae Experimentalis
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2007
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tom 67
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nr 3
3

Characterization of mice with genetically evoked selective degeneration of noradrenergic system and its possible influence on dopaminergic system

39%
Jurga A., Kreiner G., Rafa-Zablocka K., Baginska M., Parlato R., Schuetz G., Nalepa I.
Acta Neurobiologiae Experimentalis
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2013
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tom 73
|
nr 1
Parkinson’s Disease (PD) is characterized by an increased production of oxygen free radicals leading to alteration of the cellular constituents and subsequent dopaminergic cell loss within the region of substantia nigra (SN) and ventral tegmental area (VTA). However, it is well known that PD is not only associated with dopaminergic transmission. Involvement of extranigral structures in PD includes the noradrenergic system as well. Post-mortem studies of human brains revealed that neuronal loss associated with PD may proceed and is even greater in the region of locus ceruleus (LC) than SN/ VTA. In PD animal models, the loss of noradrenaline made worse the dopamine nigrostriatal damage and, in opposite, an enhanced noradrenaline level may have a neuroprotective role. The aim of this study was to determine whether genetically evoked, selective loss of noradrenergic neurons may have any long-term, negative impact on the dopaminergic system. We applied the conditional inactivation of the gene encoding transcription factor TIF-IA (essential for the regulation of rRNA synthesis) by the Cre-loxP system to induce the progressive and selective loss of noradrenergic neurons which was achieved by expressing Cre recombinase under dopamine beta-hydroxylase (DBH) promoter. Resulting TIFIADBHCre mice were born at expected rates, viable but showed clear signs of noradrenergic innervations failure e.g. ptosis, reduced locomotor activity, growth retardance and shorten life span. The animals were analyzed at 8 and 12 weeks of age. The selective loss of noradrenergic neurons was confirmed by immunofluorescent staining with the anti-tyrosine hydroxylase (TH) antibody. We observed approx. 90% reduction of TH positive cells in the LC of 8 weeks TIF-IADBHCre mice. The number of TH+ cells was not changed in the region of SN/VTA, neither in 8 nor 12 week old mutants. However, our preliminary data indicate that lack of the noradrenergic transmission may lead to enhanced expression of selected markers associated with neurodegeneration within the region of SN/VTA. Namely, we have found 1.4 fold up-regulation of mRNA encoding for glial fibrillary acidic protein (GFAP) as revealed by quantitative real-time PCR and increased level of oxidative stress shown by immunoblot detection of carbonyl groups by Western Blot in the SN/VTA of 12 weeks TIF-IADBHCre mice compared to control animals. If we provide additional evidences that selective noradrenergic degeneration affects functioning of dopaminergic neurons, TIF-IADBHCre mice may became a valuable, new model for study possible anti-PD treatment at early stages of the disease as dopaminergic neurons in these mice are not directly affected by the mutation. As for today, there are no experimental studies on a possible long-term negative impact of progressive noradrenergic degeneration on other neurotransmitter systems despite of clinically observed concomitant loss of SN/VTA and LC neurons in PD. This study was supported by the grant no 2011/03/B/NZ7/05949 financed by National Science Centre and statutory funds of the Institute of Pharmacology, Polish Academy of Sciences.
4

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

39%
Kreiner G., Chmielarz P., Kusmierczyk J., Parlato R., Schuetz G., Nalepa I.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
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.
5

Evaluation of transgenic mice with progressive degeneration of noradrenergic system towards the study of presymtomatic phase of Parkinson's disease

33%
Barut J., Chmielarz P., Jurga A., Baginska M., Parlato R., Domanskyi A., Nalepa I., Kreiner G.
Acta Neurobiologiae Experimentalis
|
2019
|
tom 79
|
nr Suppl.1
Parkinson’s disease (PD) is characterized by an inevitable loss of dopaminergic cells.However, examination of human brain tissues revealed that noradrenergic cell loss in the region of the locus coeruleus (LC) may proceed and may be even greater than dopaminergic degeneration. AIM(S): The aim of this study was to determine whether genetically evoked, selective loss of LC noradrenergic neurons in a progressive manner may negatively influence the dopaminergic system. Our mice models have progressive degeneration of the noradrenergic system, based on deletion of the gene Rrn3 encoding transcription factor TIF-IA, which is essential for the regulation of rRNA synthesis. METHOD(S): First, we applied the conditional inactivation of the Rrn3 by the Cre-loxP system expressing Cre recombinase under DBH promoter. TIF‑IADBHCre mice revealed ptosis, reduced locomotor activity, and a shortened life span associated with enhanced expression of various neurodegenerative markers within the dopaminergic system, including upregulation of micro- and astroglia, pro-inflammatory proteins, and enhanced level of oxidative stress. To limit mutations to the CNS, in a second model a Cre-dependent lentiviral vector carrying the Rrn3 deletion created by the CRISPR/Cas9 system was directly delivered to LC of DBHCre mice. RESULTS: Our construct was first successfully tested in vitro on primary dopamine neurons followed by in vivo stereotactic application. This approach seems to be successful as, in preliminary data, we observed the disintegration of nucleoli in transduced noradrenergic neurons in LC, which is the determinant of the functional impairment of the targeted TIF‑IA. CONCLUSIONS: To-date, there are no experimental studies on possible long-term negative impacts of progressive noradrenergic degeneration on other neurotransmitter systems, despite the clinically observed concomitant loss of SN/VTA and LC neurons in PD. If we provide additional evidence, mice with ongoing neurodegeneration of LC neurons may became a valuable tool for studying the presymptomatic phase of PD.
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