The synaptophysin/synaptobrevin interaction critically depends on the cholesterol content

Mitter, Diana; Reisinger, Clemens; Hinz, Britta; Hollmann, Susanne; Yelamanchili, Sowmya V.; Treiber-Held, Stephanie; Ohm, Thomas G.; Herrmann, Andreas; Ahnert‐Hilger, Gudrun

doi:10.1046/j.1471-4159.2003.01258.x

Cited by 117 publications

(85 citation statements)

References 26 publications

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“…The extent of overlapping is likely determined by the relative proportion of endosomal and plasma membrane routes present in a cell domain (Zakharenko et al, 1999), the developmental status of the cell (Rafuse et al, 2000), the affinities of the synaptic vesicle proteins for different adaptors, the association of several vesicle antigens in complexes with other SV proteins (Bennett et al, 1992), the lipid composition of the membrane (Mitter et al, 2003), and the functional status of the synapse (Heuser and Reese, 1973).…”

Section: Discussionmentioning

confidence: 99%

The Zinc Transporter ZnT3 Interacts with AP-3 and It Is Preferentially Targeted to a Distinct Synaptic Vesicle Subpopulation

Salazar

Love

Werner

et al. 2004

MBoC

112

178

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Synaptic vesicles (SV) are generated by two different mechanisms, one AP-2 dependent and one AP-3 dependent. It has been uncertain, however, whether these mechanisms generate SV that differ in molecular composition. We explored this hypothesis by analyzing the targeting of ZnT3 and synaptophysin both to PC12 synaptic-like microvesicles (SLMV) as well as SV isolated from wild-type and AP-3-deficient mocha brains. ZnT3 cytosolic tail interacted selectively with AP-3 in cell-free assays. Accordingly, pharmacological disruption of either AP-2-or AP-3-dependent SLMV biogenesis preferentially reduced synaptophysin or ZnT3 targeting, respectively; suggesting that these antigens were concentrated in different vesicles. As predicted, immuno-isolated SLMV revealed that ZnT3 and synaptophysin were enriched in different vesicle populations. Likewise, morphological and biochemical analyses in hippocampal neurons indicated that these two antigens were also present in distinct but overlapping domains. ZnT3 SV content was reduced in AP-3-deficient neurons, but synaptophysin was not altered in the AP-3 null background. Our evidence indicates that neuroendocrine cells assemble molecularly heterogeneous SV and suggests that this diversity could contribute to the functional variety of synapses. INTRODUCTIONThe molecular diversity in total brain synaptic vesicle (SV) composition is generally presumed to result from differential expression of synaptic vesicle membrane proteins in different brain regions. However, the possibility that synaptic vesicles differ in composition because of different biogenesis mechanisms has not been explored. Different vesiculation pathways could result in molecularly diverse synaptic vesicles. Vesiculation mechanisms are known to produce distinct cargo carriers from a population of donor membranes (Bonifacino and Dell'Angelica, 1999;Springer et al., 1999;Boehm and Bonifacino, 2001). This process is achieved by adaptor complexes that recognize and concentrate specific membrane proteins in the donor membranes (Bonifacino and Dell 'Angelica, 1999;Kirchhausen, 1999). PC12 cells have been shown to possess two such adaptor-dependent pathways for the assembly of synaptic vesicles, also known as synaptic-like microvesicles (SLMV) (Shi et al., 1998;de Wit et al., 1999;Jarousse and Kelly, 2001). In one pathway, SLMV are generated from the plasma membrane by a vesiculation mechanism that requires the adaptor AP-2, clathrin, and the GTPase dynamin (Shi et al., 1998). In the second pathway, SLMV are generated from endosomes by the adaptor complex AP-3 (Faundez et al., 1998;Blumstein et al., 2001) and the GTPase ARF1 (Faundez et al., 1997). In contrast to the plasma membrane pathway, the endosomederived mechanism is highly sensitive to brefeldin A (BFA) (Shi et al., 1998).Phenotypes observed in the AP-3-deficient mocha mouse are consistent with a role for the AP-3-dependent, endosome-derived pathway in neurons (Kantheti et al., 1998). The mocha mossy fibers are devoid of both the synaptic vesiclespecific zinc transpor...

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Section: Discussionmentioning

confidence: 99%

The Zinc Transporter ZnT3 Interacts with AP-3 and It Is Preferentially Targeted to a Distinct Synaptic Vesicle Subpopulation

Salazar

Love

Werner

et al. 2004

MBoC

112

178

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“…It was demonstrated that (1) cholesterol itself regulates the availability of synaptic vesicles via a direct interaction with synaptophysin (Thiele et al, 2000), (2) SNAP receptor (SNARE) complex formation is cholesterol-dependent (Lang et al, 2001;Mitter et al, 2003), and (3) the association of SNARE complex with lipid rafts regulates exocytosis (Sala͐n et al, 2005). Presynaptic proteins are increased in cholesterol-rich lipid raft fractions concomitantly with cortical development (data not shown).…”

Section: Cholesterol Synthesized In Response To Bdnf Accumulates In Lmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor Regulates Cholesterol Metabolism for Synapse Development

Suzuki¹,

Kiyosue²,

Hazama³

et al. 2007

Journal of Neuroscience

151

121

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Brain-derived neurotrophic factor (BDNF) exerts multiple biological functions in the CNS. Although BDNF can control transcription and protein synthesis, it still remains open to question whether BDNF regulates lipid biosynthesis. Here we show that BDNF elicits cholesterol biosynthesis in cultured cortical and hippocampal neurons. Importantly, BDNF elicited cholesterol synthesis in neurons, but not in glial cells. Quantitative reverse transcriptase-PCR revealed that BDNF stimulated the transcription of enzymes in the cholesterol biosynthetic pathway. BDNF-induced cholesterol increases were blocked by specific inhibitors of cholesterol synthesis, mevastatin and zaragozic acid, suggesting that BDNF stimulates de novo synthesis of cholesterol rather than the incorporation of extracellular cholesterol. Because cholesterol is a major component of lipid rafts, we investigated whether BDNF would increase the cholesterol content in lipid rafts or nonraft membrane domains. Interestingly, the BDNF-mediated increase in cholesterol occurred in rafts, but not in nonrafts, suggesting that BDNF promotes the development of neuronal lipid rafts. Consistent with this notion, BDNF raised the level of the lipid raft marker protein caveolin-2 in rafts. Remarkably, BDNF increased the levels of presynaptic proteins in lipid rafts, but not in nonrafts. An electrophysiological study revealed that BDNF-dependent cholesterol biosynthesis plays an important role for the development of a readily releasable pool of synaptic vesicles. Together, these results suggest a novel role for BDNF in cholesterol metabolism and synapse development.

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“…Since cholesterol secreted by astrocytes and transported by apoEcontaining lipoproteins mediates synapse-promoting effects [42][43][44], any reduction in cholesterol delivery might lead to degeneration of synapses. Astrocyte-delivered cholesterol also contributes to the biogenesis and cycling of synaptic vesicles and synaptophysin is a cholesterol-binding protein [45,46]. Thus, synaptophysin may function with cholesterol in renewing synaptic-vesicle membranes [46], suggesting that cholesterol availability is critical for synaptic vesicle docking and fusion [45].…”

Section: Reduced Cholesterolssecretionmentioning

confidence: 99%

“…Astrocyte-delivered cholesterol also contributes to the biogenesis and cycling of synaptic vesicles and synaptophysin is a cholesterol-binding protein [45,46]. Thus, synaptophysin may function with cholesterol in renewing synaptic-vesicle membranes [46], suggesting that cholesterol availability is critical for synaptic vesicle docking and fusion [45]. Although there is regional variation in the glial influence on synapse development and neurite outgrowth [47], data from brain slice and primary neuron cultures also suggest a critical role for astrocyte-derived signals, including astrocyte-secreted cholesterol, as endogenous modulators of neurotransmission in both cortex and hippocampus [47,48].…”

Section: Reduced Cholesterolssecretionmentioning

confidence: 99%

Apolipoprotein E4 domain interaction: Synaptic and cognitive deficits in mice

Zhong

Scearce‐Levie

Ramaswamy

et al. 2008

Alzheimer's & Dementia

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BackgroundApolipoprotein E4 (apoE4), the major genetic risk factor for Alzheimer's disease (AD) and other neurodegenerative diseases, has three structural and biophysical properties that distinguish it from the other isoforms—domain interaction, reduced stability, and lack of cysteine. Assessing their relative contributions to effects of apoE4‐associated pathogenesis in AD is important from a mechanistic and therapeutic perspective, that is not possible using human apoE transgene or knock‐in models.MethodsWe analyzed Arg‐61 apoE mice, a gene‐targeted model that selectively displays domain interaction.ResultsThe mice displayed age‐dependent loss of the synaptic protein synaptophysin in neocortex and hippocampus and had lower levels of the postsynaptic neuroligin‐1. Activation of dentate gyrus granule neurons increased Arc expression 3.5‐fold in wildtype mice but only 2.3‐fold in Arg‐61 mice. The losses of synaptic proteins caused a mild memory deficit in Arg‐61 mice in the water‐maze test. Since synaptic integrity requires efficient glutamate uptake, we measured astrocyte glutamate transporter 1 in the hippocampus. The level was reduced in Arg‐61 mice, suggesting that inefficient glutamate uptake by astrocytes causes chronic excitotoxicity. Consistent with the reduced secretion of Arg‐61 apoE by astrocytes in this model, cholesterol secretion was also reduced 34%. This reduction could also contribute to the synaptic deficits by limiting the availability of cholesterol for neuronal repair.ConclusionsDomain interaction in the absence of other structural characteristics of apoE4 is sufficient to cause synaptic pathology and functional synaptic deficits, potentially associated with astrocyte dysfunction and impaired maintenance of neurons. Therapeutic targeting of domain interaction might blunt effects of apoE4 in neurodegenerative disease.

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The synaptophysin/synaptobrevin interaction critically depends on the cholesterol content

Cited by 117 publications

References 26 publications

The Zinc Transporter ZnT3 Interacts with AP-3 and It Is Preferentially Targeted to a Distinct Synaptic Vesicle Subpopulation

The Zinc Transporter ZnT3 Interacts with AP-3 and It Is Preferentially Targeted to a Distinct Synaptic Vesicle Subpopulation

Brain-Derived Neurotrophic Factor Regulates Cholesterol Metabolism for Synapse Development

Apolipoprotein E4 domain interaction: Synaptic and cognitive deficits in mice

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