Membrane traffic in myelinating oligodendrocytes

Krämer, Eva-Maria; Schardt, Anke; Nave, Klaus‐Armin

doi:10.1002/jemt.1050

Cited by 94 publications

(97 citation statements)

References 153 publications

(165 reference statements)

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“…Functional ablation of VAMP3 and VAMP7 interfered with PLP transport in oligodendrocytes. LE/Lys localization of PLP and VAMP7 is consistent with the literature (Advani et al, 1999;Krämer et al, 2001;Feldmann et al, 2009). It has been shown that PLP accumulates in LE/Lys on clathrin-independent cholesterol-dependent endocytosis, and furthermore, retranslocation of PLP from LE/Lys storage sites to the plasma membrane is regulated by RhoGTPase inactivation triggered by a soluble neuronal signal Kippert et al, 2007).…”

Section: Discussionsupporting

confidence: 89%

“…Thus, the analysis of primary tissue always comprises both isoforms (as we have no evidence that the isoforms behave differently with regard to trafficking, the acronym PLP is used throughout the study). Inside cells, PLP is localizing to LE/ Lys (Krämer et al, 2001;Trajkovic et al, 2006), and thus we anticipated its colocalization with VAMP7 in this compartment. However, although VAMP7 antibodies clearly recognized endog- enously expressed VAMP7 in Western blots (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The cellular mechanisms of myelin formation are not well understood, but indeed essential to fully grasp pathology of myelin disease and to tackle the problem of inefficient remyelination associated with most diseases including multiple sclerosis. A major challenge for oligodendrocytes, which ensheath multiple axon segments simultaneously, is the temporal and spatial orchestration of myelin membrane synthesis and traffic to control membrane domain morphogenesis and the directed growth of the emerging myelin sheath (Krämer et al, 2001;Baron and Hoekstra, 2010). Several myelin proteins undergo distinct endocytic sorting and recycling associated with plasma membrane remodeling (Winterstein et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Transport of the Major Myelin Proteolipid Protein Is Directed by VAMP3 and VAMP7

Feldmann¹,

Amphornrat²,

Schönherr³

et al. 2011

J. Neurosci.

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CNS myelination by oligodendrocytes requires directed transport of myelin membrane components and a timely and spatially controlled membrane expansion. In this study, we show the functional involvement of the R-soluble N-ethylmaleimide-sensitive factor attachment protein receptor (R-SNARE) proteins VAMP3/cellubrevin and VAMP7/TI-VAMP in myelin membrane trafficking. VAMP3 and VAMP7 colocalize with the major myelin proteolipid protein (PLP) in recycling endosomes and late endosomes/lysosomes, respectively. Interference with VAMP3 or VAMP7 function using small interfering RNA-mediated silencing and exogenous expression of dominantnegative proteins diminished transport of PLP to the oligodendroglial cell surface. In addition, the association of PLP with myelin-like membranes produced by oligodendrocytes cocultured with cortical neurons was reduced. We furthermore identified Syntaxin-4 and Syntaxin-3 as prime acceptor Q-SNAREs of VAMP3 and VAMP7, respectively. Analysis of VAMP3-deficient mice revealed no myelination defects. Interestingly, AP-3␦-deficient mocha mice, which suffer from impaired secretion of lysosome-related organelles and missorting of VAMP7, exhibit a mild dysmyelination characterized by reduced levels of select myelin proteins, including PLP. We conclude that PLP reaches the cell surface via at least two trafficking pathways with distinct regulations: (1) VAMP3 mediates fusion of recycling endosomederived vesicles with the oligodendroglial plasma membrane in the course of the secretory pathway; (2) VAMP7 controls exocytosis of PLP from late endosomal/lysosomal organelles as part of a transcytosis pathway. Our in vivo data suggest that exocytosis of lysosomerelated organelles controlled by VAMP7 contributes to myelin biogenesis by delivering cargo to the myelin membrane.

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transport of the Major Myelin Proteolipid Protein Is Directed by VAMP3 and VAMP7

Feldmann¹,

Amphornrat²,

Schönherr³

et al. 2011

J. Neurosci.

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“…After initial recognition of the axon by the glial process, wrapping necessitates the coordination of myelin membrane generation and directed process outgrowth accompanied by reorganization of the cytoskeleton (Wilson and Brophy, 1989;Pfeiffer et al, 1993;Kramer et al, 1997Kramer et al, , 2001Song et al, 2001a). In the present study we have shown that the interaction of the Src-family tyrosine kinase Fyn and the microtubule-binding protein Tau is an important component of process formation by oligodendrocytes.…”

Section: Discussionmentioning

confidence: 55%

Process Outgrowth of Oligodendrocytes Is Promoted by Interaction of Fyn Kinase with the Cytoskeletal Protein Tau

Klein¹,

Krämer²,

et al. 2002

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Fyn kinase plays an important role during myelination and has been shown to promote morphological differentiation of cultured oligodendrocytes. We analyzed the downstream targets of Fyn kinase in oligodendrocytes. Because process outgrowth and wrapping of axons involve cytoskeletal rearrangement, we focused on cytoskeletal proteins linked to Fyn. Here we demonstrate that Fyn binds to the cytoskeletal proteins Tau and ␣-Tubulin in oligodendrocytes. Tau interacts with the Fyn SH3 domain whereas ␣-Tubulin binds to the Fyn SH2 and SH3 domains. To study the function of the Fyn-Tau interaction in oligodendrocytes, we designed a Tau deletion mutant that would compete with endogenous Tau-Fyn binding in transfected cells. The mutant Tau protein binds to the Fyn SH3 domain but lacks the microtubuli interaction domain and thus cannot bind to microtubuli. In the presence of the mutant Tau protein, a reduction of the process number and process length in oligodendroglial cells was observed. This effect is likely to be caused by interference with the Fyn-Tau-microtubuli cascade rather than inactivation of the kinase, because Fyn bound to the mutant Tau retains activity. A similar inhibition of process outgrowth was observed when oliogodendroglial cells were cultured in the presence of Fumonisin B1, an inhibitor of sphingolipid synthesis that prevents the formation of rafts. Because ligation of the cell adhesion molecule F3 on oligodendrocytes leads to activation of Fyn kinase localized in rafts, these findings suggest that recruitment of Tau and Tubulin to activated Fyn kinase in rafts is an important step in the initiation of myelination. Key words: myelination; oligodendrocytes; Fyn kinase; cytoskeleton; Tau; glycosphingolipid-rich raftsThe myelination of axons by oligodendrocytes involves the coordinated recognition of the axonal surface, ensheathment of the axonal process, and ultimately compaction of the wrappings of oligodendroglial membrane to generate the myelin sheath. The interplay of the adhesion molecules expressed by oligodendrocytes and axons as well as the downstream signal transduction cascades mediating these complex cellular interactions still remain primarily unelucidated (Pedraza et al., 2001).Substantial evidence exists that Fyn expressed by oligodendrocytes plays an important role in myelination. Mice deficient for Fyn kinase are hypomyelinated (Umemori et al., 1994;). In addition, knock-in mice expressing a kinase-defective Fyn protein that cannot be activated because of a mutation in the ATP-binding site of Fyn show severe myelination defects . Inhibition of the Fyn activity in cultured oligodendrocytes using kinase inhibitors or dominant negative Fyn constructs inhibited the process outgrowth of the cells (Osterhout et al., 1999). We have shown that in oligodendrocytes [as in neurons (Zisch et al., 1995)] the F3 adhesion molecule is complexed to the Src-family tyrosine kinase Fyn and that this association takes place within glycosphingolipid (gsl)/cholesterol-rich microdomains (Kramer et al., 1999), ge...

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“…Our attempts to coimmunoprecipitate the two proteins from brain lysates have failed (data not shown). Although this would not exclude a direct molecular interaction, we suggest that SIRT2 is indirectly associated with PLP/DM20 in membrane lipid rafts that are important for oligodendroglial membrane sorting (Kramer et al, 2001;Lee, 2001). …”

Section: Myelin Proteomicsmentioning

confidence: 73%

Proteolipid Protein Is Required for Transport of Sirtuin 2 into CNS Myelin

Werner

Kuhlmann

Shen³

et al. 2007

J. Neurosci.

228

267

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Mice lacking the expression of proteolipid protein (PLP)/DM20 in oligodendrocytes provide a genuine model for spastic paraplegia (SPG-2). Their axons are well myelinated but exhibit impaired axonal transport and progressive degeneration, which is difficult to attribute to the absence of a single myelin protein. We hypothesized that secondary molecular changes in PLP null myelin contribute to the loss of PLP/DM20-dependent neuroprotection and provide more insight into glia-axonal interactions in this disease model. By gel-based proteome analysis, we identified Ͼ160 proteins in purified myelin membranes, which allowed us to systematically monitor the CNS myelin proteome of adult PLP null mice, before the onset of disease. We identified three proteins of the septin family to be reduced in abundance, but the nicotinamide adenine dinucleotide (NAD ϩ )-dependent deacetylase sirtuin 2 (SIRT2) was virtually absent. SIRT2 is expressed throughout the oligodendrocyte lineage, and immunoelectron microscopy revealed its association with myelin. Loss of SIRT2 in PLP null was posttranscriptional, suggesting that PLP/DM20 is required for its transport into the myelin compartment. Because normal SIRT2 activity is controlled by the NAD ϩ /NADH ratio, its function may be coupled to the axo-glial metabolism and the long-term support of axons by oligodendrocytes.

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Membrane traffic in myelinating oligodendrocytes

Cited by 94 publications

References 153 publications

Transport of the Major Myelin Proteolipid Protein Is Directed by VAMP3 and VAMP7

Transport of the Major Myelin Proteolipid Protein Is Directed by VAMP3 and VAMP7

Process Outgrowth of Oligodendrocytes Is Promoted by Interaction of Fyn Kinase with the Cytoskeletal Protein Tau

Proteolipid Protein Is Required for Transport of Sirtuin 2 into CNS Myelin

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