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991.
Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells 总被引:1,自引:0,他引:1
Israel MA Yuan SH Bardy C Reyna SM Mu Y Herrera C Hefferan MP Van Gorp S Nazor KL Boscolo FS Carson CT Laurent LC Marsala M Gage FH Remes AM Koo EH Goldstein LS 《Nature》2012,482(7384):216-220
Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-β precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-β(1-40), phospho-tau(Thr?231) and active glycogen synthase kinase-3β (aGSK-3β). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not γ-secretase inhibitors, caused significant reductions in phospho-Tau(Thr?231) and aGSK-3β levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-β, in GSK-3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients. 相似文献
992.
Firestone AJ Weinger JS Maldonado M Barlan K Langston LD O'Donnell M Gelfand VI Kapoor TM Chen JK 《Nature》2012,484(7392):125-129
The conversion of chemical energy into mechanical force by AAA+ (ATPases associated with diverse cellular activities) ATPases is integral to cellular processes, including DNA replication, protein unfolding, cargo transport and membrane fusion. The AAA+ ATPase motor cytoplasmic dynein regulates ciliary trafficking, mitotic spindle formation and organelle transport, and dissecting its precise functions has been challenging because of its rapid timescale of action and the lack of cell-permeable, chemical modulators. Here we describe the discovery of ciliobrevins, the first specific small-molecule antagonists of cytoplasmic dynein. Ciliobrevins perturb protein trafficking within the primary cilium, leading to their malformation and Hedgehog signalling blockade. Ciliobrevins also prevent spindle pole focusing, kinetochore-microtubule attachment, melanosome aggregation and peroxisome motility in cultured cells. We further demonstrate the ability of ciliobrevins to block dynein-dependent microtubule gliding and ATPase activity in vitro. Ciliobrevins therefore will be useful reagents for studying cellular processes that require this microtubule motor and may guide the development of additional AAA+ ATPase superfamily inhibitors. 相似文献
993.
994.
Gibaud T Barry E Zakhary MJ Henglin M Ward A Yang Y Berciu C Oldenbourg R Hagan MF Nicastro D Meyer RB Dogic Z 《Nature》2012,481(7381):348-351
From determining the optical properties of simple molecular crystals to establishing the preferred handedness in highly complex vertebrates, molecular chirality profoundly influences the structural, mechanical and optical properties of both synthetic and biological matter on macroscopic length scales. In soft materials such as amphiphilic lipids and liquid crystals, the competition between local chiral interactions and global constraints imposed by the geometry of the self-assembled structures leads to frustration and the assembly of unique materials. An example of particular interest is smectic liquid crystals, where the two-dimensional layered geometry cannot support twist and chirality is consequently expelled to the edges in a manner analogous to the expulsion of a magnetic field from superconductors. Here we demonstrate a consequence of this geometric frustration that leads to a new design principle for the assembly of chiral molecules. Using a model system of colloidal membranes, we show that molecular chirality can control the interfacial tension, an important property of multi-component mixtures. This suggests an analogy between chiral twist, which is expelled to the edges of two-dimensional membranes, and amphiphilic surfactants, which are expelled to oil-water interfaces. As with surfactants, chiral control of interfacial tension drives the formation of many polymorphic assemblages such as twisted ribbons with linear and circular topologies, starfish membranes, and double and triple helices. Tuning molecular chirality in situ allows dynamical control of line tension, which powers polymorphic transitions between various chiral structures. These findings outline a general strategy for the assembly of reconfigurable chiral materials that can easily be moved, stretched, attached to one another and transformed between multiple conformational states, thus allowing precise assembly and nanosculpting of highly dynamical and designable materials with complex topologies. 相似文献
995.
Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts 总被引:1,自引:0,他引:1
Y Shiba S Fernandes WZ Zhu D Filice V Muskheli J Kim NJ Palpant J Gantz KW Moyes H Reinecke B Van Biber T Dardas JL Mignone A Izawa R Hanna M Viswanathan JD Gold MI Kotlikoff N Sarvazyan MW Kay CE Murry MA Laflamme 《Nature》2012,489(7415):322-325
Transplantation studies in mice and rats have shown that human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) can improve the function of infarcted hearts, but two critical issues related to their electrophysiological behaviour in vivo remain unresolved. First, the risk of arrhythmias following hESC-CM transplantation in injured hearts has not been determined. Second, the electromechanical integration of hESC-CMs in injured hearts has not been demonstrated, so it is unclear whether these cells improve contractile function directly through addition of new force-generating units. Here we use a guinea-pig model to show that hESC-CM grafts in injured hearts protect against arrhythmias and can contract synchronously with host muscle. Injured hearts with hESC-CM grafts show improved mechanical function and a significantly reduced incidence of both spontaneous and induced ventricular tachycardia. To assess the activity of hESC-CM grafts in vivo, we transplanted hESC-CMs expressing the genetically encoded calcium sensor, GCaMP3 (refs 4, 5). By correlating the GCaMP3 fluorescent signal with the host ECG, we found that grafts in uninjured hearts have consistent 1:1 host–graft coupling. Grafts in injured hearts are more heterogeneous and typically include both coupled and uncoupled regions. Thus, human myocardial grafts meet physiological criteria for true heart regeneration, providing support for the continued development of hESC-based cardiac therapies for both mechanical and electrical repair. 相似文献
996.
J Song C Zhong MA Bonaguidi GJ Sun D Hsu Y Gu K Meletis ZJ Huang S Ge G Enikolopov K Deisseroth B Luscher KM Christian GL Ming H Song 《Nature》2012,489(7414):150-154
Adult neurogenesis arises from neural stem cells within specialized niches. Neuronal activity and experience, presumably acting on this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor proliferation to new neuron maturation, synaptic integration and survival. It is unknown whether local neuronal circuitry has a direct impact on adult neural stem cells. Here we show that, in the adult mouse hippocampus, nestin-expressing radial glia-like quiescent neural stem cells (RGLs) respond tonically to the neurotransmitter γ-aminobutyric acid (GABA) by means of γ2-subunit-containing GABAA receptors. Clonal analysis of individual RGLs revealed a rapid exit from quiescence and enhanced symmetrical self-renewal after conditional deletion of γ2. RGLs are in close proximity to terminals expressing 67-kDa glutamic acid decarboxylase (GAD67) of parvalbumin-expressing (PV+) interneurons and respond tonically to GABA released from these neurons. Functionally, optogenetic control of the activity of dentate PV+ interneurons, but not that of somatostatin-expressing or vasoactive intestinal polypeptide (VIP)-expressing interneurons, can dictate the RGL choice between quiescence and activation. Furthermore, PV+ interneuron activation restores RGL quiescence after social isolation, an experience that induces RGL activation and symmetrical division. Our study identifies a niche cell–signal–receptor trio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adult neural stem cells in response to neuronal activity and experience. 相似文献
997.
998.
999.
Herman MA Peroni OD Villoria J Schön MR Abumrad NA Blüher M Klein S Kahn BB 《Nature》2012,484(7394):333-338
1000.
Beck PG Montalban J Kallinger T De Ridder J Aerts C García RA Hekker S Dupret MA Mosser B Eggenberger P Stello D Elsworth Y Frandsen S Carrier F Hillen M Gruberbauer M Christensen-Dalsgaard J Miglio A Valentini M Bedding TR Kjeldsen H Girouard FR Hall JR Ibrahim KA 《Nature》2012,481(7379):55-57
When the core hydrogen is exhausted during stellar evolution, the central region of a star contracts and the outer envelope expands and cools, giving rise to a red giant. Convection takes place over much of the star's radius. Conservation of angular momentum requires that the cores of these stars rotate faster than their envelopes; indirect evidence supports this. Information about the angular-momentum distribution is inaccessible to direct observations, but it can be extracted from the effect of rotation on oscillation modes that probe the stellar interior. Here we report an increasing rotation rate from the surface of the star to the stellar core in the interiors of red giants, obtained using the rotational frequency splitting of recently detected 'mixed modes'. By comparison with theoretical stellar models, we conclude that the core must rotate at least ten times faster than the surface. This observational result confirms the theoretical prediction of a steep gradient in the rotation profile towards the deep stellar interior. 相似文献