1,721,085 research outputs found
Dopaminergic neuronal death via necroptosis in Parkinson's disease: A review of the literature
Full text link: Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive dysfunction and loss of dopaminergic neurons of the substantia nigra pars compacta (SNc). Several pathways of programmed cell death are likely to play a role in dopaminergic neuron death, such as apoptosis, necrosis, pyroptosis and ferroptosis, as well as cell death associated with proteasomal and mitochondrial dysfunction. A better understanding of the molecular mechanisms underlying dopaminergic neuron death could inform the design of drugs that promote neuron survival. Necroptosis is a recently characterized regulated cell death mechanism that exhibits morphological features common to both apoptosis and necrosis. It requires activation of an intracellular pathway involving receptor-interacting protein 1 kinase (RIP1 kinase, RIPK1), receptor-interacting protein 3 kinase (RIP3 kinase, RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL). The potential involvement of this programmed cell death pathway in the pathogenesis of PD has been studied by analysing biomarkers for necroptosis, such as the levels and oligomerization of phosphorylated RIPK3 (pRIPK3) and phosphorylated MLKL (pMLKL), in several PD preclinical models and in PD human tissue. Although there is evidence that other types of cell death also have a role in DA neuron death, most studies support the hypothesis that this cell death mechanism is activated in PD tissues. Drugs that prevent or reduce necroptosis may provide neuroprotection for PD. In this review, we summarize the findings from these studies. We also discuss how manipulating necroptosis might open a novel therapeutic approach to reduce neuronal degeneration in PD
Synaptic Mechanisms and Protein Synthesis in Memory
No full textLearning and memory are fundamental higher brain functions that allow individuals to adapt to the environment, build up their own history as unique creatures, and widen the personal cultural background, and, ultimately, the population culture. The molecular and cellular mechanisms that contribute to short- and long-term memory are extremely conserved across evolution from mollusks to man and among various forms of memory and consist short- to long-lived rearrangements in synaptic efficiency and in the structure of neuronal networks
Identification of a developmentally regulated pathway of membrane retrieval in neuronal growth cones
No full textThe growth-cone plasma membrane constantly reconfigures during axon navigation and upon target recognition. The identity and regulation of the membrane pathway(s) participating in remodeling of the growth-cone surface remain elusive. Here, we identify a constitutive, high-capacity plasma-membrane-recycling activity in the axonal growth cones, which is mediated by a novel bulk endocytic pathway that is mechanistically related to macropinocytosis. This pathway generates large compartments at sites of intense actin-based membrane ruffling through the actions of phosphatidylinositol 3-kinase, the small GTPase Rac1 and the pinocytic chaperone Pincher. At early developmental stages, bulk endocytosis is the primary endocytic pathway for rapid retrieval of the growth-cone plasma membrane. At later stages, during the onset of synaptogenesis, an intrinsic program of maturation leads to downregulation of basal bulk endocytosis and the emergence of depolarization-induced synaptic-vesicle exo-endocytosis. We propose that the control of bulk membrane retrieval contributes to the homeostatic regulation of the axonal plasma membrane and to growth-cone remodeling during axonal outgrowth. In addition, we suggest that the downregulation of bulk endocytosis during synaptogenesis might contribute to the preservation of synaptic-vesicle specificity
Fluorescence resonance energy transfer detection of synaptophysin I and vesicle-associated membrane protein-2 interactions during exocytosis from single live synapses.
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