Chen H, Polo S, Di Fiore PP, De Camilli PV.
Rapid Ca2+-dependent decrease of protein ubiquitination at synapses.
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14908-13.
PubMed.
This paper demonstrates rapid Ca2+-dependent de-ubiquitination of synaptic proteins. Using a classical biochemical preparation of synaptosomes, which are pinched-off nerve terminals with attached postsynaptic elements capable of neurotransmitter release, De Camilli and colleagues demonstrate that strong depolarization (a stimulus that triggers neurotransmitter release followed by rapid endocytosis of synaptic vesicles) causes a rapid loss of ubiquitinated proteins, likely due to "de-ubiquitination." They demonstrate that two prominent endocytic proteins—Epsin1 and Eps15—are among the proteins subject to depolarization- and Ca2+-dependent de-ubiquitination, and provide strong evidence that the enzyme that clips off ubiquitin from Epsin is the deubiquitinating enzyme fat facets/FAM. The authors perform biochemical experiments to assess what functional effect ubiquitination has on Epsin, and show that ubiquitin-conjugated Epsin is less capable of binding lipid membranes, clathrin, and AP-2—the essential molecular ingredients for synaptic vesicle endocytosis. From these data, the authors propose that Ca2+-dependent de-ubiquitination of endocytic proteins in the presynaptic nerve terminal helps mediate the rapid endocytosis of synaptic vesicles necessary to sustain synaptic transmission.
The ubiquitin-proteasome system (UPS) has been implicated in numerous neurodegenerative disorders including Alzheimer’s disease (AD). Moreover, synaptic dysfunction has emerged as an important and perhaps initiating element in the early-stage pathogenesis of AD. By demonstrating a further link between the UPS and synaptic transmission in normal physiological states, the study by Chen et al. brings us closer to unifying these two models of AD pathogenesis. It will be of interest to examine the ubiquitinated state of synaptic proteins in animal models of AD and in human neuropathology.
Comments
This paper demonstrates rapid Ca2+-dependent de-ubiquitination of synaptic proteins. Using a classical biochemical preparation of synaptosomes, which are pinched-off nerve terminals with attached postsynaptic elements capable of neurotransmitter release, De Camilli and colleagues demonstrate that strong depolarization (a stimulus that triggers neurotransmitter release followed by rapid endocytosis of synaptic vesicles) causes a rapid loss of ubiquitinated proteins, likely due to "de-ubiquitination." They demonstrate that two prominent endocytic proteins—Epsin1 and Eps15—are among the proteins subject to depolarization- and Ca2+-dependent de-ubiquitination, and provide strong evidence that the enzyme that clips off ubiquitin from Epsin is the deubiquitinating enzyme fat facets/FAM. The authors perform biochemical experiments to assess what functional effect ubiquitination has on Epsin, and show that ubiquitin-conjugated Epsin is less capable of binding lipid membranes, clathrin, and AP-2—the essential molecular ingredients for synaptic vesicle endocytosis. From these data, the authors propose that Ca2+-dependent de-ubiquitination of endocytic proteins in the presynaptic nerve terminal helps mediate the rapid endocytosis of synaptic vesicles necessary to sustain synaptic transmission.
The ubiquitin-proteasome system (UPS) has been implicated in numerous neurodegenerative disorders including Alzheimer’s disease (AD). Moreover, synaptic dysfunction has emerged as an important and perhaps initiating element in the early-stage pathogenesis of AD. By demonstrating a further link between the UPS and synaptic transmission in normal physiological states, the study by Chen et al. brings us closer to unifying these two models of AD pathogenesis. It will be of interest to examine the ubiquitinated state of synaptic proteins in animal models of AD and in human neuropathology.
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