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During development of the nervous system, the fate of stem cells is regulated by a cell surface receptor called Notch. Notch is also present in the adult mammalian brain; however, because Notch null mice die during embryonic development, it has proven difficult to determine the functions of Notch. Here, we used Notch antisense transgenic mice that develop and reproduce normally, but exhibit reduced levels of Notch, to demonstrate a role for Notch signaling in synaptic plasticity. Mice with reduced Notch levels exhibit impaired long-term potentiation (LTP) at hippocampal CA1 synapses. A Notch ligand enhances LTP in normal mice and corrects the defect in LTP in Notch antisense transgenic mice. Levels of basal and stimulation-induced NF-κB activity were significantly decreased in mice with reduced Notch levels. These findings suggest an important role for Notch signaling in a form of synaptic plasticity known to be associated with learning and memory processes.

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Clathrin assembly lymphoid myeloid leukemia protein (CALM) is a clathrin assembly protein with a domain structure similar to the neuron-specific assembly protein AP180. We have previously found that CALM is expressed in neurons and present in synapses. We now report that CALM has a neuron-related function: it facilitates the endocytosis of the synaptic vesicle protein VAMP2 from the plasma membrane. Overexpression of CALM leads to the reduction of cell surface VAMP2, whereas knockdown of CALM by RNA interference results in the accumulation of surface VAMP2. The AP180 N-terminal homology (ANTH) domain of CALM is required for its effect on VAMP2 trafficking, and the ANTH domain itself acts as a dominant-negative mutant. Thus, our results reveal a role for CALM in directing VAMP2 trafficking during endocytosis. Neurotransmitter release is crucial to neuron function. In the presynaptic terminal, neurotransmitter release begins with the fusion of synaptic vesicles (SV) to the presynaptic plasma membrane (1). SV fusion is mediated by the SNARE proteins, which include the VAMP2 (also known as synap-tobrevin 2) on the vesicle and syntaxin 1 and SNAP25 on the plasma membrane (2,3). A recent quantitative analysis of SV constituents reveals a startling abundance of VAMP2 on SV, twice that of the next most abundant SV protein-synaptophysin (4). This finding emphasizes the importance of VAMP2 for SV. A fundamental question concerning the function of SV is how the neuron precisely constitutes and effectively preserves the vesicle components. Following SV fusion and subsequent exocytosis to release neurotransmitters, the retrieval of SV components that have dispersed to the presynaptic plasma membrane is thought to be accomplished primarily by clathrin-mediated endocytosis (5-7). Live cell image studies of hippocampal neurons show that surface VAMP2, most of which originates from SV, does not confine itself to the fusion site; instead, the protein diffuses along the axonal membrane even beyond the synapse (8,9). Although there is no doubt that endocytosis plays an indispensable role in the retrieval of SV components, it is unclear exactly how the SV acquires and maintains the individual SV-associated proteins-including VAMP2-through repeated cycles of exocytosis and endocytosis. Studies of Caenorhabditis elegans (10,11) and Drosophila (12) mutants have associated the loss of functional assembly protein (AP)180 with the misplacement of VAMP2 from its usual location on SV to the plasma membrane. AP180, a clathrin assembly protein, has been well characterized for its function in promoting the assembly of clathrin-coated vesicles at the plasma membrane (13,14). The membrane accumulation of VAMP2 in the AP180 mutants suggests that the assembly protein AP180, at least in Caenorhabditis elegans and Drosophila, has a specialized role in recruiting and directing VAMP2 from the plasma membrane to SV during endocytosis. Clathrin assembly lymphoid myeloid leukemia protein (CALM) is a clathrin assembly protein that structurally resembles A...

Here we review the examples of great longevity and potential immortality in the earliest animal types and contrast and compare these to humans and other higher animals. We start by discussing aging in single-celled organisms such as yeast and ciliates, and the idea of the immortal cell clone. Then we describe how these cell clones could become organized into colonies of different cell types that lead to multicellular animal life. We survey aging and longevity in all of the basal metazoan groups including ctenophores (comb jellies), sponges, placozoans, cnidarians (hydras, jellyfish, corals and sea anemones) and myxozoans. Then we move to the simplest bilaterian animals (with a head, three body cell layers, and bilateral symmetry), the two phyla of flatworms. A key determinant of longevity and immortality in most of these simple animals is the large numbers of pluripotent stem cells that underlie the remarkable abilities of these animals to regenerate and rejuvenate themselves. Finally, we discuss briefly the evolution of the higher bilaterians and how longevity was reduced and immortality lost due to attainment of greater body complexity and cell cycle strategies that protect these complex organisms from developing tumors. We also briefly consider how the evolution of multiple aging-related mechanisms/pathwayshinders our ability to understand and modify the aging process in higher organisms.

Mutations in a-synuclein cause some cases of familial Parkinson's disease (PD), but the mechanism by which a-synuclein promotes degeneration of dopamine-producing neurons is unknown. We report that human neural cells expressing mutant a-synuclein (A30P and A53T) have higher plasma membrane ion permeability. The higher ion permeability caused by mutant a-synuclein would be because of relatively large pores through which most cations can pass non-selectively.

Neurons and especially their synapses often project long thin processes that can invaginate neighboring neuronal or glial cells. These “invaginating projections” can occur in almost any combination of postsynaptic, presynaptic, and glial processes. Invaginating projections provide a precise mechanism for one neuron to communicate or exchange material exclusively at a highly localized site on another neuron, e.g., to regulate synaptic plasticity. The best-known types are postsynaptic projections called “spinules” that invaginate into presynaptic terminals. Spinules seem to be most prevalent at large very active synapses. Here, we present a comprehensive review of all kinds of invaginating projections associated with both neurons in general and more specifically with synapses; we describe them in all animals including simple, basal metazoans. These structures may have evolved into more elaborate structures in some higher animal groups exhibiting greater synaptic plasticity. In addition to classic spinules and filopodial invaginations, we describe a variety of lesser-known structures such as amphid microvilli, spinules in giant mossy terminals and en marron/brush synapses, the highly specialized fish retinal spinules, the trophospongium, capitate projections, and fly gnarls, as well as examples in which the entire presynaptic or postsynaptic process is invaginated. These various invaginating projections have evolved to modify the function of a particular synapse, or to channel an effect to one specific synapse or neuron, without affecting those nearby. We discuss how they function in membrane recycling, nourishment, and cell signaling and explore how they might change in aging and disease.