Expression of Proteins Linked to Exocytosis and Neurotransmission in Patients with Creutzfeldt–Jakob Disease

Ferrer, Isidró; Rivera, Rosa María Baños; Blanco, R.; Mart, E.

doi:10.1006/nbdi.1998.0226

Cited by 45 publications

(25 citation statements)

References 34 publications

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“…Regulation of syntaxin 1 levels may contribute to the mechanism underlying learning and memory, since changes in syntaxin 1 levels have been found to correlate with long term potentiation and various learning and memory behaviors (20 -22). Alteration in syntaxin 1 expression levels has been associated with several neurodegenerative diseases and psychiatric disorders, including schizophrenia, Alzheimer's disease, and Creutzfeldt-Jakob disease (23)(24)(25)(26).Despite the importance of the regulation of syntaxin 1 levels in synaptic function and dysfunction, the molecular mechanisms underlying such regulation remain undefined. To identify proteins that regulate syntaxin 1, we carried out a search in rat brain for proteins that interact with syntaxin 1 using yeast two-hybrid screens.…”

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Staring, a Novel E3 Ubiquitin-Protein Ligase That Targets Syntaxin 1 for Degradation

Chin

Vavalle

Lian

2002

Journal of Biological Chemistry

110

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Syntaxin 1 is an essential component of the neurotransmitter release machinery, and regulation of syntaxin 1 expression levels is thought to contribute to the mechanism underlying learning and memory. However, the molecular events that control the degradation of syntaxin 1 remain undefined. Here we report the identification and characterization of a novel RING finger protein, Staring, that interacts with syntaxin 1. Staring is expressed throughout the brain, where it exists in both cytosolic and membrane-associated pools. Staring binds and recruits the brain-enriched E2 ubiquitin-conjugating enzyme UbcH8 to syntaxin 1 and facilitates the ubiquitination and proteasome-dependent degradation of syntaxin 1. These findings suggest that Staring is a novel E3 ubiquitin-protein ligase that targets syntaxin 1 for degradation by the ubiquitin-proteasome pathway.Modulation of protein degradation is a major mechanism by which cells regulate the expression levels of specific proteins and consequently the cellular processes that these proteins participate in (1, 2). The ubiquitin-proteasome pathway plays a crucial role in the degradation of proteins involved in a variety of cellular processes, including differentiation, proliferation, and apoptosis. However, the role of the ubiquitin-proteasome pathway in the degradation of presynaptic proteins remains poorly characterized, despite the presence of ubiquitin at nerve terminals (3-5). In the ubiquitin-proteasome pathway, substrates are marked for degradation by covalent linkage to ubiquitin. The ubiquitinated substrate proteins are then recognized and degraded by the 26 S proteasome (1, 2, 6). Ubiquitination involves a highly specific enzyme cascade in which ubiquitin is first activated by an E1 1 ubiquitin-activating enzyme and then transferred to an E2 ubiquitin-conjugating enzyme and finally ligated to the substrate by an E3 ubiquitin-protein ligase (1,7,8). The E3 ubiquitin-protein ligase plays an essential role in determining the specificity of ubiquitination and subsequent protein degradation. Consistent with this role, it is estimated that an organism such as a human contains over 100 E3 ubiquitin ligases, in contrast to a single E1 ubiquitin-activating enzyme and about a dozen E2 ubiquitin-conjugating enzymes (9). Despite the importance of E3 ubiquitin-protein ligases in specific protein degradation and the estimated presence of more than 100 E3 ligases in the human genome, only a few E3 ligases have been characterized at the molecular level.Syntaxin 1 is a neuronal membrane protein that was originally identified as a binding partner for synaptotagmin and the N-type calcium channel (10 -12). It is well established that syntaxin 1 functions as a synaptic t-SNARE to mediate synaptic vesicle exocytosis at nerve terminals (13)(14)(15). Syntaxin 1 appears early during embryonic development (16, 17), and its expression level is dramatically up-regulated during synapse formation and brain maturation (16 -19). Regulation of syntaxin 1 levels may contribute to the mechanism unde...

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confidence: 99%

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confidence: 99%

Staring, a Novel E3 Ubiquitin-Protein Ligase That Targets Syntaxin 1 for Degradation

Chin

Vavalle

Lian

2002

Journal of Biological Chemistry

110

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“…The vacuoles that give the spongiform character of the degeneration are mainly located in dendrites, which also show varicosities and loss of spines as revealed in Golgi-impregnated specimen (2). In addition to these dendritic changes, reduced expression of presynaptic marker proteins, such as synaptophysin, synaptic-associated protein of molecular weight 25,000 (SNAP-25), 1 syntaxin 1, synapsin 1, and ␣-and ␤-synuclein, has been reported in both clinical materials (3)(4)(5)(6) and animal experimental models (7,8) indicating that presynaptic axon terminals are also affected. The mechanisms behind the presynaptic changes and their potential pathogenetic role in the disease are not known.…”

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confidence: 87%

Altered Interaction and Expression of Proteins Involved in Neurosecretion in Scrapie-infected GT1-1 Cells

Sandberg

Lőw

2005

Journal of Biological Chemistry

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Institutet, Retzius vä g 8 B2: 5, Stockholm, Sweden Prions cause transmissible and fatal diseases that are associated with spongiform degeneration, astrogliosis, and loss of axon terminals in the brains. To determine the expression of proteins involved in neurosecretion and synaptic functions after prion infection, gonadotropin-releasing hormone neuronal cell line subclone (GT1-1) was infected with the RML scrapie strain and analyzed by Western blotting, real time PCR, and immunohistochemistry. As revealed by Western blotting of lysates exposed to different temperatures, the levels of complexed SNAP-25, syntaxin 1A, and synaptophysin were decreased in scrapie-infected GT1-1 cells (ScGT1-1), whereas the level of monomeric forms of these proteins was increased and correlated to the level of scrapie prion protein (PrP Sc ). However, when complex formation was prevented by prolonged heating of samples in SDS, the levels of monomeric SNAP-25, syntaxin 1A and synaptophysin in ScGT1-1 cells were de- Prion diseases are neurodegenerative diseases that can be transmissible, inherited, or of sporadic occurrence. They are neuropathologically characterized by a marked astrogliosis, spongiform degeneration, and neuronal loss in the brain (for review see Ref. 1). The vacuoles that give the spongiform character of the degeneration are mainly located in dendrites, which also show varicosities and loss of spines as revealed in Golgi-impregnated specimen (2). In addition to these dendritic changes, reduced expression of presynaptic marker proteins, such as synaptophysin, synaptic-associated protein of molecular weight 25,000 (SNAP-25), 1 syntaxin 1, synapsin 1, and ␣-and ␤-synuclein, has been reported in both clinical materials (3-6) and animal experimental models (7,8) indicating that presynaptic axon terminals are also affected. The mechanisms behind the presynaptic changes and their potential pathogenetic role in the disease are not known. In order to clarify this, a cell culture system would be advantageous.The GT1-1 cell line is an immortalized mouse hypothalamic gonadotropin-releasing neuronal cell line (9) and represents one of the few cell lines that can be successfully infected by prions (10). These GT1-1 cells express not only key proteins involved in the regulation of secretory exocytosis such as synaptotagmin, synaptobrevin, and SNAP-25, but also synaptophysin that is localized in the membrane of small synaptic vesicles (11). Using this cell system, we have recently reported an impaired function of voltage-gated N-type calcium channels in prion-infected cells (12). Several studies have shown that synaptic vesicle release proteins, i.e. syntaxin 1A and SNAP-25, can interact with presynaptic calcium channels (13, 14) and it has also been reported that these synaptic proteins can modulate the function of presynaptic channels (15)(16)(17)(18). In the present study we asked whether alterations in the expression of proteins involved in neurosecretion or synaptic vesicle release could be observed in prion-infected GT1-1 c...

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“…70 Again parallels are found between bench experiments and CJD patients, since defective synaptic machinery in infected brains (mainly (SNAP-25), syntaxin-1 and synapsin-1) was demonstrated several years ago. 27,71 However, whether these changes affect the symptoms and the evolution of the illness requires additional study. In this regard, recent approaches analyzing gene expression changes in different rodent models lacking PrP C , 18,72 and the comparison with CJD patients and prion infected animals [73][74][75][76] main problem so far resides in our lack of knowledge of the functional relevance of these interactions.…”

Section: Emerging Roles Of Prp C : Modulating Neurotransmitter Receptmentioning

confidence: 99%

“…From a neurological point of view, prionopathies were characterized as synaptic diseases. 27 Indeed, in CJD, an abnormal form of PrP C accumulates at synaptic terminals, 28 and physiological PrP C function is lost. Several authors consider this as showing simply that physiological processes in prionopathies such as CJD are the result of the increased pathological effects of the misfolded protein PrP SC together with the loss of natural functions of the decreased PrP C .…”

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Unraveling the neuroprotective mechanisms of PrP^Cin excitotoxicity

Llorens

Rı́o

2012

Prion

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Expression of Proteins Linked to Exocytosis and Neurotransmission in Patients with Creutzfeldt–Jakob Disease

Cited by 45 publications

References 34 publications

Staring, a Novel E3 Ubiquitin-Protein Ligase That Targets Syntaxin 1 for Degradation

Staring, a Novel E3 Ubiquitin-Protein Ligase That Targets Syntaxin 1 for Degradation

Altered Interaction and Expression of Proteins Involved in Neurosecretion in Scrapie-infected GT1-1 Cells

Unraveling the neuroprotective mechanisms of PrP^Cin excitotoxicity

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Expression of Proteins Linked to Exocytosis and Neurotransmission in Patients with Creutzfeldt–Jakob Disease

Cited by 45 publications

References 34 publications

Staring, a Novel E3 Ubiquitin-Protein Ligase That Targets Syntaxin 1 for Degradation

Staring, a Novel E3 Ubiquitin-Protein Ligase That Targets Syntaxin 1 for Degradation

Altered Interaction and Expression of Proteins Involved in Neurosecretion in Scrapie-infected GT1-1 Cells

Unraveling the neuroprotective mechanisms of PrPCin excitotoxicity

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Unraveling the neuroprotective mechanisms of PrP^Cin excitotoxicity