Objective
Mounting evidence suggests that α‐synuclein, a major protein component of Lewy bodies (LB), may be responsible for initiating and spreading the pathological process in Parkinson disease ...(PD). Supporting this concept, intracerebral inoculation of synthetic recombinant α‐synuclein fibrils can trigger α‐synuclein pathology in mice. However, it remains uncertain whether the pathogenic effects of recombinant synthetic α‐synuclein may apply to PD‐linked pathological α‐synuclein and occur in species closer to humans.
Methods
Nigral LB‐enriched fractions containing pathological α‐synuclein were purified from postmortem PD brains by sucrose gradient fractionation and subsequently inoculated into the substantia nigra or striatum of wild‐type mice and macaque monkeys. Control animals received non‐LB fractions containing soluble α‐synuclein derived from the same nigral PD tissue.
Results
In both mice and monkeys, intranigral or intrastriatal inoculations of PD‐derived LB extracts resulted in progressive nigrostriatal neurodegeneration starting at striatal dopaminergic terminals. No neurodegeneration was observed in animals receiving non‐LB fractions from the same patients. In LB‐injected animals, exogenous human α‐synuclein was quickly internalized within host neurons and triggered the pathological conversion of endogenous α‐synuclein. At the onset of LB‐induced degeneration, host pathological α‐synuclein diffusely accumulated within nigral neurons and anatomically interconnected regions, both anterogradely and retrogradely. LB‐induced pathogenic effects required both human α‐synuclein present in LB extracts and host expression of α‐synuclein.
Interpretation
α‐Synuclein species contained in PD‐derived LB are pathogenic and have the capacity to initiate a PD‐like pathological process, including intracellular and presynaptic accumulations of pathological α‐synuclein in different brain areas and slowly progressive axon‐initiated dopaminergic nigrostriatal neurodegeneration. ANN NEUROL 2014;75:351–362
The centrosome linker component C‐Nap1 (encoded by CEP250) anchors filaments to centrioles that provide centrosome cohesion by connecting the two centrosomes of an interphase cell into a single ...microtubule organizing unit. The role of the centrosome linker during development of an animal remains enigmatic. Here, we show that male CEP250−/− mice are sterile because sperm production is abolished. Premature centrosome separation means that germ stem cells in CEP250−/− mice fail to establish an E‐cadherin polarity mark and are unable to maintain the older mother centrosome on the basal site of the seminiferous tubules. This failure prompts premature stem cell differentiation in expense of germ stem cell expansion. The concomitant induction of apoptosis triggers the complete depletion of germ stem cells and consequently infertility. Our study reveals a role for centrosome cohesion in asymmetric cell division, stem cell maintenance, and fertility.
Synopsis
Centrosome linker protein C‐Nap1 is important for male germ stem cell maintenance in mice. Loss of C‐NAP1 causes male infertility.
Centrosome linker protein C‐Nap1 is important for the correct establishment of E‐cadherin surface polarity patterns in mitosis and for spindle orientation in male GSCs.
Loss of C‐Nap1 results in disrupted asymmetric centrosome inheritance in male GSCs, leading to premature differentiation.
Loss of C‐Nap1 prompts apoptosis in germ cells during early development, leading to infertility.
Centrosome linker protein C‐Nap1 is important for male germ stem cell maintenance in mice. Loss of C‐NAP1 causes male infertility.
Acute monocytic leukemia is a type of myeloid leukemia that develops in monocytes. The current clinical therapies for leukemia are unsatisfactory due to their side effects and nonspecificity toward ...target cells. Some lectins display antitumor activity and may specifically recognize cancer cells by binding to carbohydrate structures on their surface. Therefore, this study evaluated the response of the human monocytic leukemia cell lines THP‐1 to the Olneya tesota PF2 lectin. The induction of apoptosis and reactive oxygen species production in PF2‐treated cells was evaluated by flow cytometry, and the lectin‐THP‐1 cell interaction and mitochondrial membrane potential were evaluated by confocal fluorescence microscopy. PF2 genotoxicity was evaluated by DNA fragmentation analysis via gel electrophoresis. The results showed that PF2 binds to THP‐1 cells, triggers apoptosis and DNA degradation, changes the mitochondrial membrane potential, and increases reactive oxygen species levels in PF2‐treated THP‐1 cells. These results suggest the potential use of PF2 for developing alternative anticancer treatments with enhanced specificity.
The folding of the mammalian cerebral cortex into sulci and gyri is thought to be favored by the amplification of basal progenitor cells and their tangential migration. Here, we provide a molecular ...mechanism for the role of migration in this process by showing that changes in intercellular adhesion of migrating cortical neurons result in cortical folding. Mice with deletions of FLRT1 and FLRT3 adhesion molecules develop macroscopic sulci with preserved layered organization and radial glial morphology. Cortex folding in these mutants does not require progenitor cell amplification but is dependent on changes in neuron migration. Analyses and simulations suggest that sulcus formation in the absence of FLRT1/3 results from reduced intercellular adhesion, increased neuron migration, and clustering in the cortical plate. Notably, FLRT1/3 expression is low in the human cortex and in future sulcus areas of ferrets, suggesting that intercellular adhesion is a key regulator of cortical folding across species.
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•Flrt1/3 double-knockout mice develop macroscopic cortical sulci•Cortex folding in mutant mice does not require progenitor cell amplification•Absence of FLRT1/3 reduces intercellular adhesion and promotes immature neuron migration•FLRT1/3 levels are low in the cortices of human embryos and future sulci of the ferret
Physical migration of neurons can create the folded cortical surface characteristic of primate brains.
Cerebral cortex size differs dramatically between reptiles, birds, and mammals, owing to developmental differences in neuron production. In mammals, signaling pathways regulating neurogenesis have ...been identified, but genetic differences behind their evolution across amniotes remain unknown. We show that direct neurogenesis from radial glia cells, with limited neuron production, dominates the avian, reptilian, and mammalian paleocortex, whereas in the evolutionarily recent mammalian neocortex, most neurogenesis is indirect via basal progenitors. Gain- and loss-of-function experiments in mouse, chick, and snake embryos and in human cerebral organoids demonstrate that high Slit/Robo and low Dll1 signaling, via Jag1 and Jag2, are necessary and sufficient to drive direct neurogenesis. Attenuating Robo signaling and enhancing Dll1 in snakes and birds recapitulates the formation of basal progenitors and promotes indirect neurogenesis. Our study identifies modulation in activity levels of conserved signaling pathways as a primary mechanism driving the expansion and increased complexity of the mammalian neocortex during amniote evolution.
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•Neurogenesis in mammalian neocortex is largely indirect, direct in reptiles and birds•Low Robo and high Dll1 signaling is necessary for indirect neurogenesis•Blocking Robo and increased Dll1 in non-mammals induces indirect neurogenesis and SVZ•High Robo–low Dll1 blocks indirect neurogenesis in human cerebral organoids
Levels of Robo and Notch signaling across amniotes determines their predominant mode of neurogenesis, with consequences on final cerebral cortex size and complexity
Going back in time with TEMPO Villalba Requena, Ana; Hippenmeyer, Simon
Neuron (Cambridge, Mass.),
02/2023, Letnik:
111, Številka:
3
Journal Article
Recenzirano
In this issue of Neuron, Espinosa-Medina et al.1 present the TEMPO (Temporal Encoding and Manipulation in a Predefined Order) system, which enables the marking and genetic manipulation of ...sequentially generated cell lineages in vertebrate species in vivo.
In this issue of Neuron, Espinosa-Medina et al.1 present the TEMPO (Temporal Encoding and Manipulation in a Predefined Order) system, which enables the marking and genetic manipulation of sequentially generated cell lineages in vertebrate species in vivo.
The experience of social stress during adolescence is associated with higher vulnerability to drug use. Increases in the acquisition of cocaine self-administration, in the escalation of ...cocaine-seeking behavior, and in the conditioned rewarding effects of cocaine have been observed in rodents exposed to repeated social defeat (RSD). In addition, prolonged or severe stress induces a proinflammatory state with microglial activation and increased cytokine production. The aim of the present work was to describe the long-term effects induced by RSD during adolescence on the neuroinflammatory response and synaptic structure by evaluating different glial and neuronal markers. In addition to an increase in the conditioned rewarding effects of cocaine, our results showed that RSD in adolescence produced inflammatory reactivity in microglia that is prolonged into adulthood, affecting astrocytes and neurons of two reward-processing areas of the brain (the prelimbic cortex, and the nucleus accumbens core). Considered as a whole these results suggest that social stress experience modulates vulnerability to suffer a loss of glia-supporting functions and neuronal functional synaptic density due to drug consumption in later life.
Los últimos treinta años fueron definitivos para que se cuestionara el concepto clásico de seguridad. En los 1990, teóricos en Copenhague, Aberystwyth y París trataron de ampliar el entendimiento ...sobre qué significa una amenaza, también sobre cómo se da el proceso de delimitación y definición de lo que se debe proteger en la política internacional —la securitización. En este artículo, con base en la historia de los conceptos, investigamos la genealogía de los dos conceptos comunes y centrales a las escuelas europeas de los estudios de seguridad, comparando y señalando sus similitudes y contrastes.
Control of cellular survival and proliferation is dependent on extracellular signals and is a prerequisite for ordered tissue development and maintenance. Activation of the cAMP responsive element ...binding protein (CREB) by phosphorylation has been implicated in the survival of mammalian cells. To define its roles in the mouse central nervous system, we disrupted Creb1 in brain of developing and adult mice using the Cre/loxP system. Mice with a Crem(-/-) background and lacking Creb in the central nervous system during development show extensive apoptosis of postmitotic neurons. By contrast, mice in which both Creb1 and Crem are disrupted in the postnatal forebrain show progressive neurodegeneration in the hippocampus and in the dorsolateral striatum. The striatal phenotype is reminiscent of Huntington disease and is consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases.
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