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  • Articles  (103)
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  • 2010-2014  (103)
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  • 101
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    Caspase activation precedes and leads to tangles (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-04-02
    Description: Studies of post-mortem tissue have shown that the location of fibrillar tau deposits, called neurofibrillary tangles (NFT), matches closely with regions of massive neuronal death, severe cytological abnormalities, and markers of caspase activation and apoptosis, leading to the idea that tangles cause neurodegeneration in Alzheimer's disease and tau-related frontotemporal dementia. However, using in vivo multiphoton imaging to observe tangles and activation of executioner caspases in living tau transgenic mice (Tg4510 strain), we find the opposite: caspase activation occurs first, and precedes tangle formation by hours to days. New tangles form within a day. After a new tangle forms, the neuron remains alive and caspase activity seems to be suppressed. Similarly, introduction of wild-type 4-repeat tau (tau-4R) into wild-type animals triggered caspase activation, tau truncation and tau aggregation. Adeno-associated virus-mediated expression of a construct mimicking caspase-cleaved tau into wild-type mice led to the appearance of intracellular aggregates, tangle-related conformational- and phospho-epitopes, and the recruitment of full-length endogenous tau to the aggregates. On the basis of these data, we propose a new model in which caspase activation cleaves tau to initiate tangle formation, then truncated tau recruits normal tau to misfold and form tangles. Because tangle-bearing neurons are long-lived, we suggest that tangles are 'off pathway' to acute neuronal death. Soluble tau species, rather than fibrillar tau, may be the critical toxic moiety underlying neurodegeneration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091360/" 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/PMC3091360/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉de Calignon, Alix -- Fox, Leora M -- Pitstick, Rose -- Carlson, George A -- Bacskai, Brian J -- Spires-Jones, Tara L -- Hyman, Bradley T -- AG 026249/AG/NIA NIH HHS/ -- AG08487/AG/NIA NIH HHS/ -- K99 AG033670/AG/NIA NIH HHS/ -- K99 AG033670-01A1/AG/NIA NIH HHS/ -- R01 AG008487/AG/NIA NIH HHS/ -- R01 AG008487-18/AG/NIA NIH HHS/ -- R01 AG026249/AG/NIA NIH HHS/ -- R01 AG026249-01/AG/NIA NIH HHS/ -- England -- Nature. 2010 Apr 22;464(7292):1201-4. doi: 10.1038/nature08890. Epub 2010 Mar 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20357768" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/metabolism/pathology ; Caspases/*metabolism ; Cell Death ; Enzyme Activation ; Humans ; Mice ; Mice, Transgenic ; Neurofibrillary Tangles/chemistry/enzymology/*metabolism/pathology ; Neurons/enzymology/metabolism/pathology ; Protein Processing, Post-Translational ; Solubility ; Time Factors ; tau Proteins/chemistry/genetics/*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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  • 102
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    Multiple native states reveal persistent ruggedness of an RNA folding landscape (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-02-05
    Description: According to the 'thermodynamic hypothesis', the sequence of a biological macromolecule defines its folded, active (or 'native') structure as a global energy minimum in the folding landscape. However, the enormous complexity of folding landscapes of large macromolecules raises the question of whether there is in fact a unique global minimum corresponding to a unique native conformation or whether there are deep local minima corresponding to alternative active conformations. The folding of many proteins is well described by two-state models, leading to highly simplified representations of protein folding landscapes with a single native conformation. Nevertheless, accumulating experimental evidence suggests a more complex topology of folding landscapes with multiple active conformations that can take seconds or longer to interconvert. Here we demonstrate, using single-molecule experiments, that an RNA enzyme folds into multiple distinct native states that interconvert on a timescale much longer than that of catalysis. These data demonstrate that severe ruggedness of RNA folding landscapes extends into conformational space occupied by native conformations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818749/" 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/PMC2818749/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Solomatin, Sergey V -- Greenfeld, Max -- Chu, Steven -- Herschlag, Daniel -- GM49243/GM/NIGMS NIH HHS/ -- P01 GM066275/GM/NIGMS NIH HHS/ -- P01 GM066275-01A1/GM/NIGMS NIH HHS/ -- P01-GM-66275/GM/NIGMS NIH HHS/ -- R01 GM049243/GM/NIGMS NIH HHS/ -- R01 GM049243-09/GM/NIGMS NIH HHS/ -- R37 GM049243/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Feb 4;463(7281):681-4. doi: 10.1038/nature08717.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20130651" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Biocatalysis ; Fluorescence Resonance Energy Transfer ; Introns/genetics ; Kinetics ; *Nucleic Acid Conformation ; Oligoribonucleotides/genetics/metabolism ; RNA, Catalytic/*chemistry/*metabolism ; Tetrahymena/enzymology/*genetics ; Thermodynamics ; Time Factors
    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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  • 103
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    Learning-related fine-scale specificity imaged in motor cortex circuits of behaving mice (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-04-09
    Description: Cortical neurons form specific circuits, but the functional structure of this microarchitecture and its relation to behaviour are poorly understood. Two-photon calcium imaging can monitor activity of spatially defined neuronal ensembles in the mammalian cortex. Here we applied this technique to the motor cortex of mice performing a choice behaviour. Head-fixed mice were trained to lick in response to one of two odours, and to withhold licking for the other odour. Mice routinely showed significant learning within the first behavioural session and across sessions. Microstimulation and trans-synaptic tracing identified two non-overlapping candidate tongue motor cortical areas. Inactivating either area impaired voluntary licking. Imaging in layer 2/3 showed neurons with diverse response types in both areas. Activity in approximately half of the imaged neurons distinguished trial types associated with different actions. Many neurons showed modulation coinciding with or preceding the action, consistent with their involvement in motor control. Neurons with different response types were spatially intermingled. Nearby neurons (within approximately 150 mum) showed pronounced coincident activity. These temporal correlations increased with learning within and across behavioural sessions, specifically for neuron pairs with similar response types. We propose that correlated activity in specific ensembles of functionally related neurons is a signature of learning-related circuit plasticity. Our findings reveal a fine-scale and dynamic organization of the frontal cortex that probably underlies flexible behaviour.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Komiyama, Takaki -- Sato, Takashi R -- O'Connor, Daniel H -- Zhang, Ying-Xin -- Huber, Daniel -- Hooks, Bryan M -- Gabitto, Mariano -- Svoboda, Karel -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Apr 22;464(7292):1182-6. doi: 10.1038/nature08897. Epub 2010 Apr 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Janelia Farm Research Campus, HHMI, Ashburn, Virginia 20147, USA. komiyamat@janelia.hhmi.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20376005" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Axonal Transport ; Behavior, Animal/*physiology ; Choice Behavior/physiology ; Learning/*physiology ; Male ; Mice ; Mice, Inbred C57BL ; Motor Cortex/*cytology/*physiology ; Motor Neurons/physiology ; Neural Pathways/*physiology ; Odors/analysis ; Pyramidal Cells/physiology ; Reward ; Stimulation, Chemical ; Time Factors ; Tongue/cytology/innervation/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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