White matter integrity in mice requires continuous myelin synthesis at the inner tongue

Meschkat, Martin; Steyer, Anna M.; Weil, Miguel; Kusch, Kathrin; Jahn, Olaf; Piepkorn, Lars; Agüi‐Gonzalez, Paola; Phan, Nhu T. N.; Ruhwedel, Torben; Sadowski, Boguslawa; Rizzoli, Silvio O.; Werner, Hauke; Ehrenreich, Hannelore; Nave, Klaus Armin; Möbius, Wiebke

doi:10.1038/s41467-022-28720-y

Cited by 51 publications

(46 citation statements)

References 96 publications

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“…Does VAMP2/3-mediated exocytosis contribute to myelin maintenance? Recent studies report the breakdown of myelin sheaths upon inducing the genetic ablation of PLP1 or MBP during adulthood, suggesting that continuous transport of new material is necessary for myelin maintenance 70 , 71 . Single-cell transcriptomics of adult and aged mice revealed that VAMP2 and VAMP3 continue to be the highest expressed v-SNAREs in oligodendrocytes through the lifetime of a mouse 72 (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes

et al. 2022

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Myelin is required for rapid nerve signaling and is emerging as a key driver of CNS plasticity and disease. How myelin is built and remodeled remains a fundamental question of neurobiology. Central to myelination is the ability of oligodendrocytes to add vast amounts of new cell membrane, expanding their surface areas by many thousand-fold. However, how oligodendrocytes add new membrane to build or remodel myelin is not fully understood. Here, we show that CNS myelin membrane addition requires exocytosis mediated by the vesicular SNARE proteins VAMP2/3. Genetic inactivation of VAMP2/3 in myelinating oligodendrocytes caused severe hypomyelination and premature death without overt loss of oligodendrocytes. Through live imaging, we discovered that VAMP2/3-mediated exocytosis drives membrane expansion within myelin sheaths to initiate wrapping and power sheath elongation. In conjunction with membrane expansion, mass spectrometry of oligodendrocyte surface proteins revealed that VAMP2/3 incorporates axon-myelin adhesion proteins that are collectively required to form nodes of Ranvier. Together, our results demonstrate that VAMP2/3-mediated membrane expansion in oligodendrocytes is indispensable for myelin formation, uncovering a cellular pathway that could sculpt myelination patterns in response to activity-dependent signals or be therapeutically targeted to promote regeneration in disease.

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Section: Discussionmentioning

confidence: 99%

CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes

et al. 2022

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“…ab137043, RRID:AB_2749817), Iba1 (Wako, catalog no. 019-19741; RRID:AB_839504), myelin basic protein ( 88 ), MCT1 ( 54 ), NeuN (Chemicon, catalog no. MAB377B, RRID:AB_177621; Millipore, catalog no.…”

Section: Methodsmentioning

confidence: 99%

Ketogenic diet uncovers differential metabolic plasticity of brain cells

Düking¹,

Spieth²,

Berghoff³

et al. 2022

Sci. Adv.

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To maintain homeostasis, the body, including the brain, reprograms its metabolism in response to altered nutrition or disease. However, the consequences of these challenges for the energy metabolism of the different brain cell types remain unknown. Here, we generated a proteome atlas of the major central nervous system (CNS) cell types from young and adult mice, after feeding the therapeutically relevant low-carbohydrate, high-fat ketogenic diet (KD) and during neuroinflammation. Under steady-state conditions, CNS cell types prefer distinct modes of energy metabolism. Unexpectedly, the comparison with KD revealed distinct cell type–specific strategies to manage the altered availability of energy metabolites. Astrocytes and neurons but not oligodendrocytes demonstrated metabolic plasticity. Moreover, inflammatory demyelinating disease changed the neuronal metabolic signature in a similar direction as KD. Together, these findings highlight the importance of the metabolic cross-talk between CNS cells and between the periphery and the brain to manage altered nutrition and neurological disease.

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“…This hypothesis is supported by the fact that at least two major myelin proteins (PLP and MBP) are shown to interact with autophagosomes, leading to the idea that CNS myelin itself could use this machinery for its degradation. Myelin synthesized during development is continuously exchanged and renewed, through a procedure named myelin turnover, by which new membranes replace old membranes, which then must be removed [ 7 , 63 ]. Our existing knowledge documents that the elimination of aberrantly deposited myelin -in case of trauma or during development as in myelin turnover- is accomplished through phagocytosis via microglia as well as endocytosis via astrocytes [ 11 , 12 , 13 ].…”

Section: Discussionmentioning

confidence: 99%

Autophagic degradation of CNS myelin maintains axon integrity

Ktena¹,

Kaplanis²,

Kolotuev³

et al. 2022

CST

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(Macro)autophagy is a major lysosome-dependent degradation mechanism which engulfs, removes and recycles unwanted cytoplasmic material, including damaged organelles and toxic protein aggregates. Although a few studies implicate autophagy in CNS demyelinating pathologies, its role, particularly in mature oligodendrocytes and CNS myelin, remains poorly studied. Here, using both pharmacological and genetic inhibition of the autophagic machinery, we provide evidence that autophagy is an essential mechanism for oligodendrocyte maturation in vitro. Our study reveals that two core myelin proteins, namely proteolipid protein (PLP) and myelin basic protein (MBP) are incorporated into autophagosomes in oligodendrocytes, resulting in their degradation. Furthermore, we ablated atg5, a core gene of the autophagic machinery, specifically in myelinating glial cells in vivo by tamoxifen administration (plp-CreERT2; atg5 f/f) and showed that myelin maintenance is perturbed, leading to PLP accumulation. Significant morphological defects in myelin membrane such as decompaction accompanied with increased axonal degeneration are observed. As a result, the mice exhibit behavioral deficits. In summary, our data highlight that the maintenance of adult myelin homeostasis in the CNS requires the involvement of a fully functional autophagic machinery.

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White matter integrity in mice requires continuous myelin synthesis at the inner tongue

Cited by 51 publications

References 96 publications

CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes

CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes

Ketogenic diet uncovers differential metabolic plasticity of brain cells

Autophagic degradation of CNS myelin maintains axon integrity

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