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Novel SCAMPs lacking NPF repeats: ubiquitous and synaptic vesicle-specific forms implicate SCAMPs in multiple membrane-trafficking functions.

ABSTRACT: In vertebrates, secretory carrier membrane proteins (SCAMPs) 1-3 constitute a family of putative membrane-trafficking proteins composed of cytoplasmic N-terminal sequences with NPF repeats, four central transmembrane regions (TMRs), and a cytoplasmic tail. SCAMPs probably function in endocytosis by recruiting EH-domain proteins to the N-terminal NPF repeats but may have additional functions mediated by their other sequences. We now demonstrate that SCAMPs form a much larger and more heterogeneous protein family than envisioned previously, with an evolutionary conservation extending to invertebrates and plants. Two novel vertebrate SCAMPs (SCAMPs 4 and 5), single SCAMP genes in Caenorhabditis elegans and Drosophila melanogaster, and multiple SCAMPs in Arabidopsis thaliana were identified. Interestingly, the novel SCAMPs 4 and 5 lack the N-terminal NPF repeats that are highly conserved in all other SCAMPs. RNA and Western blotting experiments showed that SCAMPs 1-4 are ubiquitously coexpressed, whereas SCAMP 5 is only detectable in brain where it is expressed late in development coincident with the elaboration of mature synapses. Immunocytochemistry revealed that SCAMP 5 exhibits a synaptic localization, and subcellular fractionations demonstrated that SCAMP 5 is highly enriched in synaptic vesicles. Our studies characterize SCAMPs as a heterogeneous family of putative trafficking proteins composed of three isoforms that are primarily synthesized outside of neurons (SCAMPs 2-4), one isoform that is ubiquitously expressed but highly concentrated on synaptic vesicles (SCAMP 1), and one brain-specific isoform primarily localized to synaptic vesicles (SCAMP 5). The conservation of the TMRs in all SCAMPs with the variable presence of N-terminal NPF repeats suggests that in addition to the role of some SCAMPs in endocytosis mediated by their NPF repeats, all SCAMPs perform a "core" function in membrane traffic mediated by their TMRs.

SUBMITTER: Fernandez-Chacon R

PROVIDER: S-EPMC6772721 | biostudies-literature | 2000 Nov

REPOSITORIES: biostudies-literature

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Novel SCAMPs lacking NPF repeats: ubiquitous and synaptic vesicle-specific forms implicate SCAMPs in multiple membrane-trafficking functions.

Fernández-Chacón R R Südhof T C TC

The Journal of neuroscience : the official journal of the Society for Neuroscience 20001101 21

In vertebrates, secretory carrier membrane proteins (SCAMPs) 1-3 constitute a family of putative membrane-trafficking proteins composed of cytoplasmic N-terminal sequences with NPF repeats, four central transmembrane regions (TMRs), and a cytoplasmic tail. SCAMPs probably function in endocytosis by recruiting EH-domain proteins to the N-terminal NPF repeats but may have additional functions mediated by their other sequences. We now demonstrate that SCAMPs form a much larger and more heterogeneou ...[more]

PMID: 11050114

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Project description:α-Synuclein is a presynaptic protein that regulates synaptic vesicle trafficking under physiological conditions. However, in several neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, α-synuclein accumulates throughout the neuron, including at synapses, leading to altered synaptic function, neurotoxicity, and motor, cognitive, and autonomic dysfunction. Neurons typically contain both monomeric and multimeric forms of α-synuclein, and it is generally accepted that disrupting the balance between them promotes aggregation and neurotoxicity. However, it remains unclear how distinct molecular species of α-synuclein affect synapses where α-synuclein is normally expressed. Using the lamprey reticulospinal synapse model, we previously showed that acute introduction of excess recombinant monomeric or dimeric α-synuclein impaired distinct stages of clathrin-mediated synaptic vesicle endocytosis, leading to a loss of synaptic vesicles. Here, we expand this knowledge by investigating the effects of native, physiological α-synuclein isolated from the brain of a neuropathologically normal human subject, which comprised predominantly helically folded multimeric α-synuclein with a minor component of monomeric α-synuclein. After acute introduction of excess brain-derived human α-synuclein, there was a moderate reduction in the synaptic vesicle cluster and an increase in the number of large, atypical vesicles called "cisternae." In addition, brain-derived α-synuclein increased synaptic vesicle and cisternae sizes and induced atypical fusion/fission events at the active zone. In contrast to monomeric or dimeric α-synuclein, the brain-derived multimeric α-synuclein did not appear to alter clathrin-mediated synaptic vesicle endocytosis. Taken together, these data suggest that excess brain-derived human α-synuclein impairs intracellular vesicle trafficking and further corroborate the idea that different molecular species of α-synuclein produce distinct trafficking defects at synapses. These findings provide insights into the mechanisms by which excess α-synuclein contributes to synaptic deficits and disease phenotypes.

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Novel SCAMPs lacking NPF repeats: ubiquitous and synaptic vesicle-specific forms implicate SCAMPs in multiple membrane-trafficking functions.

Publications

Novel SCAMPs lacking NPF repeats: ubiquitous and synaptic vesicle-specific forms implicate SCAMPs in multiple membrane-trafficking functions.

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