Modulation of receptor cycling by neuron-enriched endosomal protein of 21 kD

Steiner, Pascal; Sarria, J.-C. Floyd; Glauser, Liliane; Magnin, Sarah; Catsicas, Stefan; Hirling, Harald

doi:10.1083/jcb.200202022

Cited by 109 publications

(214 citation statements)

References 41 publications

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“…Functional studies suggest a primary role for NEEP21 in endocytic recycling with respect to seventransmembrane, ion channel, and cell adhesion type receptors (18,44,45). In contrast, our data indicate a preferential role for calcyon in CME.…”

Section: Discussioncontrasting

confidence: 55%

Calcyon, a Novel Partner of Clathrin Light Chain, Stimulates Clathrin-mediated Endocytosis

Xiao

Dai

Négyessy

et al. 2006

Journal of Biological Chemistry

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In the central nervous system, clathrin-mediated endocytosis is crucial for efficient synaptic transmission. Clathrin-coated vesicle assembly and disassembly is regulated by some 30 adaptor and accessory proteins, most of which interact with clathrin heavy chain. Using the calcyon cytosolic domain as bait, we isolated clathrin light chain in a yeast two-hybrid screen. The interaction domain was mapped to the heavy chain binding domain and C-terminal regions of light chain. Further, the addition of the calcyon C terminus stimulated clathrin self-assembly in a dose-dependent fashion. Calcyon, which is a single transmembrane protein predominantly expressed in brain, localized to vesicular compartments within preand postsynaptic structures. There was a high degree of overlap in the distribution of LC and calcyon in neuronal dendrites, spines, and cell bodies. Co-immunoprecipitation studies further suggested an association of calcyon with the clathrin-mediated endocytic machinery. Compared with controls, HEK293 cells overexpressing calcyon exhibited significantly enhanced transferrin uptake but equivalent levels of recycling. Conversely, transferrin uptake was largely abolished in neocortical neurons obtained from mice homozygous for a calcyon null allele, whereas recycling proceeded at wild type levels. Collectively, these data indicate a role for calcyon in clathrin-mediated endocytosis in brain.In the central nervous system, clathrin-mediated endocytosis (CME) 3 is essential for pre-and postsynaptic adaptations correlated with learning and memory (1-4). In axon terminals, CME is required for synaptic vesicle recycling, a process linked to optimizing levels of releasable pools of neurotransmitter during synaptic activity (4). Similarly, in dendritic spines, internalization of postsynaptic receptors via clathrin-coated vesicles (CCVs) plays a role in long term changes in synaptic strength (2, 5-7). The protein backbone of CCVs consists of clathrin triskelions assembled into a lattice structure. Each triskelion is composed of three heavy chains (HCs) and three light chains (LCs). The time and place of CCV assembly and breakdown are regulated by some 30 adaptor and accessory proteins (8), most of which are ubiquitous and interact with HC. In contrast to HC, only four proteins aside from HC are known to interact with LC, including calmodulin (9), Hsc70 (heat shock protein 70) (10), Hip1 (Huntingtin-interacting protein 1), and the closely related protein Hip1R (Hip1-related protein) (11-14). However, targeted deletion studies indicate that neuronal enriched isoforms of several adaptor and accessory proteins are essential for optimal synaptic transmission (4). The enrichment of Hip1 and calmodulin in neurons raises the possibility that adaptor and accessory protein interactions with LC might likewise be crucial determinants of efficient CME in the central nervous system.Calcyon is a single transmembrane protein predominantly expressed in the central nervous system and localized to membranous intracellular compartments wi...

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Section: Discussioncontrasting

confidence: 55%

Calcyon, a Novel Partner of Clathrin Light Chain, Stimulates Clathrin-mediated Endocytosis

Xiao

Dai

Négyessy

et al. 2006

Journal of Biological Chemistry

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“…Human and mouse homologs of the NSG1 gene encode evolutionarily conserved 21-kDa proteins (185 amino acids) with 97% amino acid sequence identity. Mammalian NSG1 protein displays about 56 and 37% identity with mammalian NSG2 and NSG3 proteins, respectively (Carlock et al, 1996;Sabéran-Djoneidi et al, 1998;Steiner et al, 2002). NSG1 significantly co-localizes with the early and recycling endosomal SNARE trafficking protein syntaxin 13 and glutamate receptor interacting protein 1 in membrane receptor recycling structures, particularly small GTPase Rab4-containing vesicles.…”

Section: Introductionmentioning

confidence: 99%

“…NSG2 is otherwise known as HMP19 protein. NSG3 is also known as dopamine receptor D1 interacting protein (DRD1IP) and calcyon neuronspecific vesicular protein (CALY) (Steiner et al, 2002;Muthusamy et al, 2009). All members of the NSG family are originally identified in the brain, and implicated in receptor endocytosis and protein trafficking in nerve cells (Steiner et al, 2002;Muthusamy et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Endocytotic receptor recycling is necessary for signal transduction during development. Endosomal trafficking, which includes docking and fusion of transport vesicles, depends on SNARE proteins, such as syntaxin 13 (Steiner et al, 2002). Many proteins have been identified as regulators of endosomal traffic in neuronal and nonneuronal endosomes (Yap et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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The distribution of neuron-specific gene family member 1 in brain and germ cells: Implications for the regulation of germ-line development by brain

et al. 2011

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Vesicular acidification at early endosomes dissociates endocytosed receptor-ligand complexes. The ligands, receptors, or both are then directed to late endosomes for degradation or recycled back to the plasma membrane. Of neuron-specific gene (NSG) family members, early endosomal protein neuron-specific gene family member 1 (NSG1) is the most important in receptor recycling. In this study, we characterized chicken NSG1 (cNSG1). We found several functional sites related to endocytotic machinery in cNSG1 that were highly conserved with most other vertebrate NSG1 proteins. We examined the tissue and duration specificity and the temporal and spatial patterns of cNSG1 expression. cNSG1 expression was preferentially located in all regions of the brain, neuroendocrine glands, and spinal cord. Unexpectedly, cNSG1 expression was strongly detected during male and female germ-line development. Expression of NSG1 in two apparently unrelated cell types such as neurons and germ cells suggests NSG1 roles in neurons and germ-cells chemotaxis and endocytotic machinery. Developmental Dynamics 240:850-861,

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“…Primary hippocampal neurons were prepared from P0 pups from mice (C57BL/6JRccHsd, Harlan) as previously described. 64 Briefly, the cerebral hippocampi were isolated stereoscopically and dissociated by trituration in medium containing papain (20 U/ml, Sigma-Aldrich). Hippocampal neurons were cultured in Neurobasal medium containing B27 supplement, L-glutamine and penicillin/streptomycin (Life Technologies).…”

Section: F(2 μM) M(18μm) + F(2μm)mentioning

confidence: 99%

Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death

et al. 2015

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The role of extracellular α-synuclein (α-syn) in the initiation and the spreading of neurodegeneration in Parkinson's disease (PD) has been studied extensively over the past 10 years. However, the nature of the α-syn toxic species and the molecular mechanisms by which they may contribute to neuronal cell loss remain controversial. In this study, we show that fully characterized recombinant monomeric, fibrillar or stabilized forms of oligomeric α-syn do not trigger significant cell death when added individually to neuroblastoma cell lines. However, a mixture of preformed fibrils (PFFs) with monomeric α-syn becomes toxic under conditions that promote their growth and amyloid formation. In hippocampal primary neurons and ex vivo hippocampal slice cultures, α-syn PFFs are capable of inducing a moderate toxicity over time that is greatly exacerbated upon promoting fibril growth by addition of monomeric α-syn. The causal relationship between α-syn aggregation and cellular toxicity was further investigated by assessing the effect of inhibiting fibrillization on α-syn-induced cell death. Remarkably, our data show that blocking fibril growth by treatment with known pharmacological inhibitor of α-syn fibrillization (Tolcapone) or replacing monomeric α-syn by monomeric β-synuclein in α-syn mixture composition prevent α-syn-induced toxicity in both neuroblastoma cell lines and hippocampal primary neurons. We demonstrate that exogenously added α-syn fibrils bind to the plasma membrane and serve as nucleation sites for the formation of α-syn fibrils and promote the accumulation and internalization of these aggregates that in turn activate both the extrinsic and intrinsic apoptotic cell death pathways in our cellular models. Our results support the hypothesis that ongoing aggregation and fibrillization of extracellular α-syn play central roles in α-syn extracellular toxicity, and suggest that inhibiting fibril growth and seeding capacity constitute a viable strategy for protecting against α-syn-induced toxicity and slowing the progression of neurodegeneration in PD and other synucleinopathies. 1 Nevertheless, the relationship between α-syn aggregation and neurodegeneration in PD remains elusive. 2A possible role for extracellular α-syn in the pathogenicity of PD emerged from the observation that newly grafted neurons in PD patients exhibit α-syn pathology similar to that of neighboring diseased cells. 3,4 Despite the consensus that α-syn is mainly an intracellular protein, α-syn has been detected in the cerebrospinal fluid under both pathological and healthy conditions. 5 In addition, in vivo rodent models and cellular studies have shown that monomers 6 and aggregated forms 6,7 of α-syn are secreted into the extracellular space via several mechanisms, 7,8 including the nonclassical endoplasmic reticulum/Golgi-independent exocytosis 8 or the exosomal route, 9,10 and are then internalized by neighboring cells. 7This suggests that extracellular α-syn may play a critical role in the spreading of α-syn pathology throughout the brai...

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Modulation of receptor cycling by neuron-enriched endosomal protein of 21 kD

Cited by 109 publications

References 41 publications

Calcyon, a Novel Partner of Clathrin Light Chain, Stimulates Clathrin-mediated Endocytosis

Calcyon, a Novel Partner of Clathrin Light Chain, Stimulates Clathrin-mediated Endocytosis

The distribution of neuron-specific gene family member 1 in brain and germ cells: Implications for the regulation of germ-line development by brain

Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death

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