Soluble amyloid-β oligomers (Aβo) trigger Alzheimer’s disease (AD) pathophysiology and bind with high affinity to cellular prion protein (PrPC). At the postsynaptic density (PSD), extracellular Aβo ...bound to lipid-anchored PrPC activates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple Aβo-PrPC with Fyn. Only coexpression of the metabotropic glutamate receptor, mGluR5, allowed PrPC-bound Aβo to activate Fyn. PrPC and mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. Aβo-PrPC generates mGluR5-mediated increases of intracellular calcium in Xenopus oocytes and in neurons, and the latter is also driven by human AD brain extracts. In addition, signaling by Aβo-PrPC-mGluR5 complexes mediates eEF2 phosphorylation and dendritic spine loss. For mice expressing familial AD transgenes, mGluR5 antagonism reverses deficits in learning, memory, and synapse density. Thus, Aβo-PrPC complexes at the neuronal surface activate mGluR5 to disrupt neuronal function.
•Among transmembrane PSD proteins, only mGluR5 couples Aβo-PrPC to Fyn kinase•mGluR5 also links Aβo-PrPC to calcium signaling and protein translation control•AD brain extract-induced dysregulation of neuronal calcium requires PrPC-mGluR5•Transgenic mouse memory deficits and synapse loss are reversed by mGluR5 antagonist
Amyloid-β oligomers trigger Alzheimer’s pathophysiology by binding to PrPC and disrupting synapses. Um et al. show that the mGluR5 metabotropic glutamate receptor links Aβo-PrPC to intracellular signaling. For AD mice, mGluR5 antagonism reverses deficits in learning, memory, and synapse density.
Neurons in distinct brain regions remodel in response to postnatal stressor exposure, and structural plasticity may underlie stress-related modifications in behavioral outcomes. Given the persistence ...of stress-related diseases such as depression, a critical next step in identifying the contributions of neural structure to psychopathology will be to identify brain circuits and cell types that fail to recover from stressor exposure. We enumerated dendritic spines during and after chronic stress hormone exposure in hippocampal CA1, deep-layer prefrontal cortex, and the basal amygdala and also reconstructed dendritic arbors of CA1 pyramidal neurons. Corticosterone modified dendritic spine density in these regions, but with the exception of the orbitofrontal cortex, densities normalized with a recovery period. Dendritic retraction of hippocampal CA1 neurons and anhedonic-like insensitivity to a sucrose solution also persisted despite a recovery period. Using mice with reduced gene dosage of p190rhogap, a cytoskeletal regulatory protein localized to dendritic spines, we next isolated structural correlates of both behavioral vulnerability (spine elimination) and resilience (spine proliferation) to corticosterone within the orbital cortex. Our findings provide novel empirical support for the perspective that stress-related structural reorganization of certain neuron populations can persist despite a "recovery" period from stressor exposure and that these modifications may lay a structural foundation for stressor vulnerability-or resiliency-across the lifespan.
In the developing brain, dendrite branches and dendritic spines form and turn over dynamically. By contrast, most dendrite arbors and dendritic spines in the adult brain are stable for months, years ...and possibly even decades. Emerging evidence reveals that dendritic spine and dendrite arbor stability have crucial roles in the correct functioning of the adult brain and that loss of stability is associated with psychiatric disorders and neurodegenerative diseases. Recent findings have provided insights into the molecular mechanisms that underlie long-term dendrite stabilization, how these mechanisms differ from those used to mediate structural plasticity and how they are disrupted in disease.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The Abl-family non-receptor tyrosine kinases are essential regulators of the cytoskeleton. They transduce diverse extracellular cues into cytoskeletal rearrangements that have dramatic effects on ...cell motility and morphogenesis. Recent biochemical and genetic studies have revealed several mechanisms that Abl-family kinases use to mediate these effects. Abl-family kinases stimulate actin polymerization through the activation of cortactin, hematopoietic lineage cell-specific protein (HS1), WASp- and WAVE-family proteins, and Rac1. They also attenuate cell contractility by inhibiting RhoA and altering adhesion dynamics. These pathways impinge on several physiological processes, including development and maintenance of the nervous and immune systems, and epithelial morphogenesis. Elucidating how Abl-family kinases are regulated, and where and when they coordinate cytoskeletal changes, is essential for garnering a better understanding of these complex processes.
Invasive carcinoma cells use specialized actin polymerization-driven protrusions called invadopodia to degrade and possibly invade through the extracellular matrix (ECM) during metastasis. ...Phosphorylation of the invadopodium protein cortactin is a master switch that activates invadopodium maturation and function. Cortactin was originally identified as a hyperphosphorylated protein in v-Src-transformed cells, but the kinase or kinases that are directly responsible for cortactin phosphorylation in invadopodia remain unknown. In this study, we provide evidence that the Abl-related nonreceptor tyrosine kinase Arg mediates epidermal growth factor (EGF)-induced cortactin phosphorylation, triggering actin polymerization in invadopodia, ECM degradation, and matrix proteolysis-dependent tumor cell invasion. Both Src and Arg localize to invadopodia and are required for EGF-induced actin polymerization. Notably, Arg overexpression in Src knockdown cells can partially rescue actin polymerization in invadopodia while Src overexpression cannot compensate for loss of Arg, arguing that Src indirectly regulates invadopodium maturation through Arg activation. Our findings suggest a novel mechanism by which an EGFR-Src-Arg-cortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. Furthermore, they identify Arg as a novel mediator of invadopodia function and a candidate therapeutic target to inhibit tumor invasion in vivo.
Dendritic spines are the receptive contacts at most excitatory synapses in the central nervous system. Spines are dynamic in the developing brain, changing shape as they mature as well as appearing ...and disappearing as they make and break connections. Spines become much more stable in adulthood, and spine structure must be actively maintained to support established circuit function. At the same time, adult spines must retain some plasticity so their structure can be modified by activity and experience. As such, the regulation of spine stability and remodeling in the adult animal is critical for normal function, and disruption of these processes is associated with a variety of late onset diseases including schizophrenia and Alzheimer's disease. The extracellular matrix (ECM), composed of a meshwork of proteins and proteoglycans, is a critical regulator of spine and synapse stability and plasticity. While the role of ECM receptors in spine regulation has been extensively studied, considerably less research has focused directly on the role of specific ECM ligands. Here, we review the evidence for a role of several brain ECM ligands and remodeling proteases in the regulation of dendritic spine and synapse formation, plasticity, and stability in adults.
Severe IgE-mediated, food-induced anaphylactic reactions are characterized by pulmonary venous vasodilatation and fluid extravasation, which are thought to lead to the life-threatening anaphylactic ...phenotype. The underlying immunologic and cellular processes involved in driving fluid extravasation and the severe anaphylactic phenotype are not fully elucidated.
We sought to define the interaction and requirement of IL-4 and vascular endothelial (VE) IL-4 receptor α chain (IL-4Rα) signaling in histamine-abelson murine leukemia viral oncogene homology 1 (ABL1)–mediated VE dysfunction and fluid extravasation in the severity of IgE-mediated anaphylactic reactions in mice.
Mice deficient in VE IL-4Rα and models of passive and active oral antigen– and IgE-induced anaphylaxis were used to define the requirements of the VE IL-4Rα and ABL1 pathway in severe anaphylactic reactions. The human VE cell line (EA.hy926 cells) and pharmacologic (imatinib) and genetic (short hairpin RNA knockdown of IL4RA and ABL1) approaches were used to define the requirement of this pathway in VE barrier dysfunction.
IL-4 exacerbation of histamine-induced hypovolemic shock in mice was dependent on VE expression of IL-4Rα. IL-4– and histamine-induced ABL1 activation in human VE cells and VE barrier dysfunction was ABL1-dependent. Development of severe IgE-mediated hypovolemia and shock required VE-restricted ABL1 expression. Treatment of mice with a history of food-induced anaphylaxis with the ABL kinase inhibitor imatinib protected the mice from severe IgE-mediated anaphylaxis.
IL-4 amplifies IgE- and histamine-induced VE dysfunction, fluid extravasation, and the severity of anaphylaxis through a VE IL-4Rα/ABL1–dependent mechanism. These studies implicate an important contribution by the VE compartment in the severity of anaphylaxis and identify a new pathway for therapeutic intervention of IgE-mediated reactions.
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β1 integrin has been shown to promote metastasis in a number of tumor models, including breast, ovarian, pancreatic, and skin cancer; however, the mechanism by which it does so is poorly understood. ...Invasive membrane protrusions called invadopodia are believed to facilitate extracellular matrix degradation and intravasation during metastasis. Previous work showed that β1 integrin localizes to invadopodia, but its role in regulating invadopodial function has not been well characterized. We find that β1 integrin is required for the formation of mature, degradation-competent invadopodia in both two- and three-dimensional matrices but is dispensable for invadopodium precursor formation in metastatic human breast cancer cells. β1 integrin is activated during invadopodium precursor maturation, and forced β1 integrin activation enhances the rate of invadopodial matrix proteolysis. Furthermore, β1 integrin interacts with the tyrosine kinase Arg and stimulates Arg-dependent phosphorylation of cortactin on tyrosine 421. Silencing β1 integrin with small interfering RNA completely abrogates Arg-dependent cortactin phosphorylation and cofilin-dependent barbed-end formation at invadopodia, leading to a significant decrease in the number and stability of mature invadopodia. These results describe a fundamental role for β1 integrin in controlling actin polymerization-dependent invadopodial maturation and matrix degradation in metastatic tumor cells.
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