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Neuromuscular synapse integrity requires linkage of acetylcholine receptors to postsynaptic intermediate filament networks via rapsyn-plectin 1f complexes.

Mihailovska E, Raith M, Valencia RG, Fischer I, Al Banchaabouchi M, Herbst R, Wiche G - Mol. Biol. Cell (2014)

Bottom Line: Live imaging of acetylcholine receptors (AChRs) in cultured myotubes differentiated ex vivo from immortalized plectin-deficient myoblasts revealed them to be highly mobile and unable to coalesce into stable clusters, in contrast to wild-type cells.In their phenotypic behavior, mutant mice closely mimicked EBS-MD-MyS patients, including impaired body balance, severe muscle weakness, and reduced life span.Our study demonstrates that linkage to desmin IF networks via plectin is crucial for formation and maintenance of AChR clusters, postsynaptic NMJ organization, and body locomotion.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.

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Schematic model of endplate regions depicting cytoskeleton anchorage in wt and plectin-deficient myofibers. (A) In normal myofibers, plectin isoform P1f, specifically bound via its N-terminal molecular domain to endplates, recruits desmin IFs (in blue) via its C-terminal IFBD; in addition, P1f interlinks IFs with DGC constituent proteins laterally along the infoldings. In a similar way, other isoforms of plectin specifically link the nuclear/ER membrane (P1), mitochondria (P1b), and Z-disks (P1d) to the IF network. In this way, a highly organized IF network mechanically integrates endplates, cytoplasmic organelles, and the contractile apparatus, stabilizing the synaptic microenvironment and enabling incorporation of AChRs into stable clusters. (B) In plectin-deficient myofibers, the IF network becomes unbound from endplates and the sarcolemma, leading to its collapse and aggregation. This causes marked architectural abnormalities of endplates (such as loss of infoldings), reduced AChR cluster stability, and profound changes in the synaptic microenvironment, including altered morphology of myonuclei (unpublished data) and mitochondria, as well as accumulation of MTs (in green).
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Figure 10: Schematic model of endplate regions depicting cytoskeleton anchorage in wt and plectin-deficient myofibers. (A) In normal myofibers, plectin isoform P1f, specifically bound via its N-terminal molecular domain to endplates, recruits desmin IFs (in blue) via its C-terminal IFBD; in addition, P1f interlinks IFs with DGC constituent proteins laterally along the infoldings. In a similar way, other isoforms of plectin specifically link the nuclear/ER membrane (P1), mitochondria (P1b), and Z-disks (P1d) to the IF network. In this way, a highly organized IF network mechanically integrates endplates, cytoplasmic organelles, and the contractile apparatus, stabilizing the synaptic microenvironment and enabling incorporation of AChRs into stable clusters. (B) In plectin-deficient myofibers, the IF network becomes unbound from endplates and the sarcolemma, leading to its collapse and aggregation. This causes marked architectural abnormalities of endplates (such as loss of infoldings), reduced AChR cluster stability, and profound changes in the synaptic microenvironment, including altered morphology of myonuclei (unpublished data) and mitochondria, as well as accumulation of MTs (in green).

Mentions: As depicted by the model shown in Figure 10A, we suggest that IFs in partnership with plectin serve NMJs in a dual way. First, they promote and consolidate postsynaptic membrane infolding by being linked to AChR/rapsyn complexes at the crest of the folds and to lateral DGCs along the sides of the folds. Second, by physically connecting the endplate region with myonuclei, mitochondria, and Z-disks (via isoforms P1, P1b, and P1d), IFs provide the stable, and at the same time flexible, subsarcolemmal microenvironment around the folds that guarantees efficient force transmission and mechanosensitivity. In contrast, when IFs retract from the endplates and collapse into aggregates in the absence of plectin, endplates lose their typically folded architecture, mobile AChRs remain loose without forming immobilized clusters, and MTs become more prominent (invading the space normally occupied by IFs; Figure 10B).


Neuromuscular synapse integrity requires linkage of acetylcholine receptors to postsynaptic intermediate filament networks via rapsyn-plectin 1f complexes.

Mihailovska E, Raith M, Valencia RG, Fischer I, Al Banchaabouchi M, Herbst R, Wiche G - Mol. Biol. Cell (2014)

Schematic model of endplate regions depicting cytoskeleton anchorage in wt and plectin-deficient myofibers. (A) In normal myofibers, plectin isoform P1f, specifically bound via its N-terminal molecular domain to endplates, recruits desmin IFs (in blue) via its C-terminal IFBD; in addition, P1f interlinks IFs with DGC constituent proteins laterally along the infoldings. In a similar way, other isoforms of plectin specifically link the nuclear/ER membrane (P1), mitochondria (P1b), and Z-disks (P1d) to the IF network. In this way, a highly organized IF network mechanically integrates endplates, cytoplasmic organelles, and the contractile apparatus, stabilizing the synaptic microenvironment and enabling incorporation of AChRs into stable clusters. (B) In plectin-deficient myofibers, the IF network becomes unbound from endplates and the sarcolemma, leading to its collapse and aggregation. This causes marked architectural abnormalities of endplates (such as loss of infoldings), reduced AChR cluster stability, and profound changes in the synaptic microenvironment, including altered morphology of myonuclei (unpublished data) and mitochondria, as well as accumulation of MTs (in green).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 10: Schematic model of endplate regions depicting cytoskeleton anchorage in wt and plectin-deficient myofibers. (A) In normal myofibers, plectin isoform P1f, specifically bound via its N-terminal molecular domain to endplates, recruits desmin IFs (in blue) via its C-terminal IFBD; in addition, P1f interlinks IFs with DGC constituent proteins laterally along the infoldings. In a similar way, other isoforms of plectin specifically link the nuclear/ER membrane (P1), mitochondria (P1b), and Z-disks (P1d) to the IF network. In this way, a highly organized IF network mechanically integrates endplates, cytoplasmic organelles, and the contractile apparatus, stabilizing the synaptic microenvironment and enabling incorporation of AChRs into stable clusters. (B) In plectin-deficient myofibers, the IF network becomes unbound from endplates and the sarcolemma, leading to its collapse and aggregation. This causes marked architectural abnormalities of endplates (such as loss of infoldings), reduced AChR cluster stability, and profound changes in the synaptic microenvironment, including altered morphology of myonuclei (unpublished data) and mitochondria, as well as accumulation of MTs (in green).
Mentions: As depicted by the model shown in Figure 10A, we suggest that IFs in partnership with plectin serve NMJs in a dual way. First, they promote and consolidate postsynaptic membrane infolding by being linked to AChR/rapsyn complexes at the crest of the folds and to lateral DGCs along the sides of the folds. Second, by physically connecting the endplate region with myonuclei, mitochondria, and Z-disks (via isoforms P1, P1b, and P1d), IFs provide the stable, and at the same time flexible, subsarcolemmal microenvironment around the folds that guarantees efficient force transmission and mechanosensitivity. In contrast, when IFs retract from the endplates and collapse into aggregates in the absence of plectin, endplates lose their typically folded architecture, mobile AChRs remain loose without forming immobilized clusters, and MTs become more prominent (invading the space normally occupied by IFs; Figure 10B).

Bottom Line: Live imaging of acetylcholine receptors (AChRs) in cultured myotubes differentiated ex vivo from immortalized plectin-deficient myoblasts revealed them to be highly mobile and unable to coalesce into stable clusters, in contrast to wild-type cells.In their phenotypic behavior, mutant mice closely mimicked EBS-MD-MyS patients, including impaired body balance, severe muscle weakness, and reduced life span.Our study demonstrates that linkage to desmin IF networks via plectin is crucial for formation and maintenance of AChR clusters, postsynaptic NMJ organization, and body locomotion.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.

Show MeSH
Related in: MedlinePlus