NOR activity in hippocampal areas during the postnatal development and ageing

Moreno, Laura; Cimadevilla, José Manuel; González-Pardo, Héctor; Zahonero, M. C.; Árias, Jorge L.

doi:10.1016/s0047-6374(97)00054-7

Cited by 20 publications

(6 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The possibility that neuronal nucleolar transcription serves as a sensor of DNA damage is supported by observations of nucleolar dysfunction/disorganization in dorsal root ganglia (DRG) neurons from rodents treated with DNA damaging anti‐cancer drugs including cisplatin, other Pt derivatives and the DNA topoisomerase‐1 (Topo1) inhibitor doxorubicin (Tomiwa et al 1986; Bigotte & Olsson 1987; McKeage et al 2001; Jamieson et al 2005). The reduced neuronal nucleolar volume indicative of RNAPol1 inhibition has been reported at the early stages of AD and during normal rodent aging (Mann et al 1988; Garcia Moreno et al 1997). In a mouse model of accelerated aging caused by the loss of the klotho gene transcript, oxidative neuronal DNA damage, reduced RNAPol1 activity and neurodegeneration were also reported (Nagai et al 2003; Anamizu et al 2005).…”

Section: Nucleolar Stress As a Neurotoxic Consequence Of Dna Damagementioning

confidence: 81%

Neurotoxic mechanisms of DNA damage: focus on transcriptional inhibition

Hetman

Vashishta

Rempała

2010

Journal of Neurochemistry

View full text Add to dashboard Cite

J. Neurochem. (2010) 114, 1537–1549. Abstract Although DNA damage‐induced neurotoxicity is implicated in various pathologies of the nervous system, its underlying mechanisms are not completely understood. Transcription is a DNA transaction that is highly active in the nervous system. In addition to its direct role in expression of the genetic information, transcription contributes to DNA damage detection and repair as well as chromatin organization including biogenesis of the nucleolus. Transcription is inhibited by DNA single‐strand breaks and DNA adducts. Hence, transcription inhibition may be an important contributor to the neurotoxic consequences of such types of DNA damage. This review discusses the existing evidence in support of the latter hypothesis. The presented literature suggests that neuronal DNA damage interferes with the RNA‐Polymerase‐2‐dependent transcription of genes encoding proteins with critical functions in neurotransmission and intracellular signaling. The latter category includes extracellular signal‐regulated kinase‐1/2 mitogen‐activated protein kinase phosphatases whose lowered expression results in chronic activation of extracellular signal‐regulated kinase‐1/2 and its reduced responsiveness to physiological stimuli. Conversely, DNA damage‐induced inhibition of RNA‐Polymerase‐1 and the subsequent disruption of the nucleolus induce p53‐mediated apoptosis of developing neurons. Finally, decreasing nucleolar transcription may link DNA damage to chronic neurodegeneration in adults.

show abstract

Section: Nucleolar Stress As a Neurotoxic Consequence Of Dna Damagementioning

confidence: 81%

Neurotoxic mechanisms of DNA damage: focus on transcriptional inhibition

Hetman

Vashishta

Rempała

2010

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…In line with a crucial role in learning and memory, rRNA transcription is down-regulated during ageing in CA1 and dentate gyrus (DG) hippocampal areas although in CA3 it is increased to compensate the functional loss in DG and CA1. Interestingly, CA1 and DG are especially vulnerable to brain injury and Alzheimer's disease (AD), supporting the connection between neuronal activity, metabolism, and functional deficits in aged hippocampal neurons (Garcia Moreno et al, 1997 ). For example, rRNA transcription is decreased in hippocampal neurons after alcohol consumption and deprivation in rats and it is associated with memory impairment (Garcia-Moreno et al, 2001 ).…”

Section: Introductionmentioning

confidence: 86%

Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons

Kiryk

Sowodniok

Kreiner

et al. 2013

Front. Cell. Neurosci.

View full text Add to dashboard Cite

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.

show abstract

“…Moreover, decline in rRNA synthesis and nucleolar size occur during aging, which is the principal risk factor for neurodegenerative diseases [19, 20]. One of the major problems in neurodegenerative diseases is that the majority of cases are sporadic and, even when an inherited basis is ascertained, there is a high inter-individual variability.…”

Section: Disruption Of Nucleolar Activity In Neurodegenerative Diseasesmentioning

confidence: 99%

Nucleolar activity in neurodegenerative diseases: a missing piece of the puzzle?

Parlato

Kreiner

2012

J Mol Med

View full text Add to dashboard Cite

Nucleoli are the sites where synthesis of rRNA and ribosomal assembly take place. Along with these "traditional" roles, the nucleolus controls cellular physiology and homeostasis. The cellular and molecular alterations associated with impaired nucleolar activity ("nucleolar stress") have just started to be systematically explored in the nervous system taking advantage of newly available animal models lacking rRNA synthesis in specific neurons. These studies showed that nucleolar function is necessary for neuronal survival and that its modality of action differs between and within cell types. Nucleolar function is also crucial in pathology as it controls mitochondrial activity and critical stress signaling pathways mimicking hallmarks of human neurodegenerative diseases. This mini-review will focus on the modes of action of nucleolar stress and discuss how the manipulation of nucleolar activity might underscore novel strategies to extend neuronal function and survival.Keywords rRNA . Nucleolus . Cellular stress . Neurodegeneration . Mouse models Non-traditional roles of the nucleolus under physiological conditionsNucleoli are non-membrane-bound structures within the nucleus where ribosomal RNA (rRNA) genes are transcribed.These atypical cellular organelles consist of three major compartments with specific functions: (1) fibrillar centers (FC, pre-rRNA synthesis), (2) dense fibrillar components (DFC, pre-RNA processing), and (3) granular components (GC, ribosome assembly). Their organization allows hosting a number of proteins and RNAs with an important role in various cellular processes. Thus the perturbation of nucleolar dynamic assembly exerts profound effects on several cellular functions [1]. A detailed description of nucleolar morphology and organization has been provided elsewhere [1,2]. Here we focus on the mechanisms by which nucleolar activity may regulate neuronal function and survival and contribute especially to neurodegenerative diseases.One intriguing mechanism to control embryonic development, differentiation, and survival is the nucleolar shuttling of cell cycle regulators and transcription factors dictating cell lineage to the nucleoplasm [1]. Moreover, rRNA repression seems required for the execution of differentiation programs. For example, during the embryonic development, transcription of rRNA genes is repressed by lineage-commitment transcription factors turning off the pluripotency genes [3]. During neural lineage commitment there is no direct evidence that rRNA transcription is inhibited; it is likely, however, that mechanisms involving nucleolar dynamics could be in play. For example in brain and retina the levels of the nucleolar protein nucleostemin, a controller of pre-rRNA processing, are rapidly reduced before cell cycle exit and neural differentiation [4,5], suggesting that rRNA biosynthesis may have a regulatory effect on neurogenesis.However, the major regulatory function associated with altered dynamics of nucleolar proteins is connected to the stress response and involv...

show abstract

NOR activity in hippocampal areas during the postnatal development and ageing

Cited by 20 publications

References 25 publications

Neurotoxic mechanisms of DNA damage: focus on transcriptional inhibition

Neurotoxic mechanisms of DNA damage: focus on transcriptional inhibition

Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons

Nucleolar activity in neurodegenerative diseases: a missing piece of the puzzle?

Contact Info

Product

Resources

About