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  • 1
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    RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-01-22
    Description: In the healthy adult brain synapses are continuously remodelled through a process of elimination and formation known as structural plasticity. Reduction in synapse number is a consistent early feature of neurodegenerative diseases, suggesting deficient compensatory mechanisms. Although much is known about toxic processes leading to synaptic dysfunction and loss in these disorders, how synaptic regeneration is affected is unknown. In hibernating mammals, cooling induces loss of synaptic contacts, which are reformed on rewarming, a form of structural plasticity. We have found that similar changes occur in artificially cooled laboratory rodents. Cooling and hibernation also induce a number of cold-shock proteins in the brain, including the RNA binding protein, RBM3 (ref. 6). The relationship of such proteins to structural plasticity is unknown. Here we show that synapse regeneration is impaired in mouse models of neurodegenerative disease, in association with the failure to induce RBM3. In both prion-infected and 5XFAD (Alzheimer-type) mice, the capacity to regenerate synapses after cooling declined in parallel with the loss of induction of RBM3. Enhanced expression of RBM3 in the hippocampus prevented this deficit and restored the capacity for synapse reassembly after cooling. RBM3 overexpression, achieved either by boosting endogenous levels through hypothermia before the loss of the RBM3 response or by lentiviral delivery, resulted in sustained synaptic protection in 5XFAD mice and throughout the course of prion disease, preventing behavioural deficits and neuronal loss and significantly prolonging survival. In contrast, knockdown of RBM3 exacerbated synapse loss in both models and accelerated disease and prevented the neuroprotective effects of cooling. Thus, deficient synapse regeneration, mediated at least in part by failure of the RBM3 stress response, contributes to synapse loss throughout the course of neurodegenerative disease. The data support enhancing cold-shock pathways as potential protective therapies in neurodegenerative disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338605/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338605/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peretti, Diego -- Bastide, Amandine -- Radford, Helois -- Verity, Nicholas -- Molloy, Colin -- Martin, Maria Guerra -- Moreno, Julie A -- Steinert, Joern R -- Smith, Tim -- Dinsdale, David -- Willis, Anne E -- Mallucci, Giovanna R -- MC_U132692719/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2015 Feb 12;518(7538):236-9. doi: 10.1038/nature14142. Epub 2015 Jan 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK. ; 1] Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK [2] Department of Clinical Neurosciences, Clifford Allbutt Building, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0AH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25607368" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/metabolism ; Animals ; Cold Shock Proteins and Peptides/metabolism ; *Cold Temperature ; Cold-Shock Response/*physiology ; Disease Models, Animal ; Hibernation/physiology ; Hippocampus/metabolism ; Male ; Mice ; Neurodegenerative Diseases/*metabolism/*pathology ; *Neuronal Plasticity ; *Neuroprotective Agents ; Prions/physiology ; RNA-Binding Proteins/genetics/*metabolism ; Regeneration ; Synapses/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Sustained translational repression by eIF2alpha-P mediates prion neurodegeneration (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-05-25
    Description: The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer's, Parkinson's and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the alpha-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2alpha-P levels are seen in patients with Alzheimer's, Parkinson's and prion diseases, but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2alpha-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2alpha-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2alpha-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2alpha-P dephosphorylation, increased eIF2alpha-P levels, exacerbating neurotoxicity and significantly reducing survival in prion-diseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378208/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378208/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moreno, Julie A -- Radford, Helois -- Peretti, Diego -- Steinert, Joern R -- Verity, Nicholas -- Martin, Maria Guerra -- Halliday, Mark -- Morgan, Jason -- Dinsdale, David -- Ortori, Catherine A -- Barrett, David A -- Tsaytler, Pavel -- Bertolotti, Anne -- Willis, Anne E -- Bushell, Martin -- Mallucci, Giovanna R -- MC_U105185860/Medical Research Council/United Kingdom -- MC_U123160654/Medical Research Council/United Kingdom -- MC_U132692719/Medical Research Council/United Kingdom -- MC_UP_A600_1023/Medical Research Council/United Kingdom -- MC_UP_A600_1024/Medical Research Council/United Kingdom -- U.1051.02.011.00001.01 (85860)/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2012 May 6;485(7399):507-11. doi: 10.1038/nature11058.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22622579" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Death/drug effects ; Cinnamates/pharmacology ; Eukaryotic Initiation Factor-2/analysis/*chemistry/*metabolism ; Hippocampus/cytology/metabolism/pathology ; Kaplan-Meier Estimate ; Mice ; Mice, Inbred C57BL ; Neurodegenerative Diseases/etiology/*metabolism/pathology ; Neurons/drug effects/pathology ; Neuroprotective Agents ; Phosphoproteins/analysis/*metabolism ; Phosphorylation ; PrPSc Proteins/analysis/metabolism/toxicity ; Prion Diseases/pathology ; Prions/biosynthesis/genetics/*metabolism ; *Protein Biosynthesis/drug effects ; Protein Folding/drug effects ; Protein Phosphatase 1/genetics/metabolism ; Repressor Proteins/analysis/chemistry/*metabolism ; Synapses/drug effects/metabolism/pathology ; Synaptic Transmission/drug effects ; Thiourea/analogs & derivatives/pharmacology ; Unfolded Protein Response/physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    microRNA-34a regulates neurite outgrowth, spinal morphology, and function (2011)
    National Academy of Sciences
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    Publication Date: 2011-12-12
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    TAp73 knockout mice show morphological and functional nervous system defects associated with loss of p75 neurotrophin receptor (2013)
    National Academy of Sciences
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    Publication Date: 2013-11-04
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    Rab11 modulates {alpha}-synuclein-mediated defects in synaptic transmission and behaviour (2015)
    Oxford University Press
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    Publication Date: 2015-01-25
    Description: A central pathological hallmark of Parkinson's disease (PD) is the presence of proteinaceous depositions known as Lewy bodies, which consist largely of the protein α-synuclein (aSyn). Mutations, multiplications and polymorphisms in the gene encoding aSyn are associated with familial forms of PD and susceptibility to idiopathic PD. Alterations in aSyn impair neuronal vesicle formation/transport, and likely contribute to PD pathogenesis by neuronal dysfunction and degeneration. aSyn is functionally associated with several Rab family GTPases, which perform various roles in vesicle trafficking. Here, we explore the role of the endosomal recycling factor Rab11 in the pathogenesis of PD using Drosophila models of aSyn toxicity. We find that aSyn induces synaptic potentiation at the larval neuromuscular junction by increasing synaptic vesicle (SV) size, and that these alterations are reversed by Rab11 overexpression. Furthermore, Rab11 decreases aSyn aggregation and ameliorates several aSyn-dependent phenotypes in both larvae and adult fruit flies, including locomotor activity, degeneration of dopaminergic neurons and shortened lifespan. This work emphasizes the importance of Rab11 in the modulation of SV size and consequent enhancement of synaptic function. Our results suggest that targeting Rab11 activity could have a therapeutic value in PD.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 6
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    Rab11 rescues synaptic dysfunction and behavioural deficits in a Drosophila model of Huntington's disease (2012)
    Oxford University Press
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    Publication Date: 2012-06-13
    Description: Synapse abnormalities in Huntington's disease (HD) patients can precede clinical diagnosis and neuron loss by decades. The polyglutamine expansion in the huntingtin (htt) protein that underlies this disorder leads to perturbations in many cellular pathways, including the disruption of Rab11-dependent endosomal recycling. Impairment of the small GTPase Rab11 leads to the defective formation of vesicles in HD models and may thus contribute to the early stages of the synaptic dysfunction in this disorder. Here, we employ transgenic Drosophila melanogaster models of HD to investigate anomalies at the synapse and the role of Rab11 in this pathology. We find that the expression of mutant htt in the larval neuromuscular junction decreases the presynaptic vesicle size, reduces quantal amplitudes and evoked synaptic transmission and alters larval crawling behaviour. Furthermore, these indicators of early synaptic dysfunction are reversed by the overexpression of Rab11. This work highlights a potential novel HD therapeutic strategy for early intervention, prior to neuronal loss and clinical manifestation of disease.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 7
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    microRNA-34a regulates neurite outgrowth, spinal morphology, and function [Cell Biology] (2011)
    National Academy of Sciences
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    Publication Date: 2011-12-28
    Description: The p53 family member TAp73 is a transcription factor that plays a key role in many biological processes, including neuronal development. In particular, we have shown that p73 drives the expression of miR-34a, but not miR-34b and c, in mouse cortical neurons. miR-34a in turn modulates the expression of synaptic targets including synaptotagmin-1 and syntaxin-1A. Here we show that this axis is retained in mouse ES cells committed to differentiate toward a neurological phenotype. Moreover, overexpression of miR-34a alters hippocampal spinal morphology, and results in electrophysiological changes consistent with a reduction in spinal function. Therefore, the TAp73/miR-34a axis has functional relevance in primary neurons. These data reinforce a role for miR-34a in neuronal development.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 8
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    Prion protein facilitates synaptic vesicle release by enhancing release probability (2014)
    Oxford University Press
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    Publication Date: 2014-08-03
    Description: The cellular prion protein (PrP C ) has been implicated in several neurodegenerative diseases as a result of protein misfolding. In humans, prion disease occurs typically with a sporadic origin where uncharacterized mechanisms induce spontaneous PrP C misfolding leading to neurotoxic PrP-scrapie formation (PrP SC ). The consequences of misfolded PrP C signalling are well characterized but little is known about the physiological roles of PrP C and its involvement in disease. Here we investigated wild-type PrP C signalling in synaptic function as well as the effects of a disease-relevant mutation within PrP C (proline-to-leucine mutation at codon 101). Expression of wild-type PrP C at the Drosophila neuromuscular junction leads to enhanced synaptic responses as detected in larger miniature synaptic currents which are caused by enlarged presynaptic vesicles. The expression of the mutated PrP C leads to reduction of both parameters compared with wild-type PrP C . Wild-type PrP C enhances synaptic release probability and quantal content but reduces the size of the ready-releasable vesicle pool. Partially, these changes are not detectable following expression of the mutant PrP C . A behavioural test revealed that expression of either protein caused an increase in locomotor activities consistent with enhanced synaptic release and stronger muscle contractions. Both proteins were sensitive to proteinase digestion. These data uncover new functions of wild-type PrP C at the synapse with a disease-relevant mutation in PrP C leading to diminished functional phenotypes. Thus, our data present essential new information possibly related to prion pathogenesis in which a functional synaptic role of PrP C is compromised due to its advanced conversion into PrP SC thereby creating a lack-of-function scenario.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 9
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    p73 regulates p75NTR [Cell Biology] (2013)
    National Academy of Sciences
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    Publication Date: 2013-11-20
    Description: Total and N-terminal isoform selective p73 knockout mice show a variety of central nervous system defects. Here we show that TAp73 is a transcriptional activator of p75 neurotrophin receptor (p75NTR) and that p75NTR mRNA and protein levels are strongly reduced in the central and peripheral nervous systems of p73 knockout...
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    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 10
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    Prion protein facilitates synaptic vesicle release by enhancing release probability (2014)
    Oxford University Press
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    Publication Date: 2014-04-09
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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