Absence of -Syntrophin Leads to Structurally Aberrant Neuromuscular Synapses Deficient in Utrophin

Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 10/2000; 150(6):1385-98. DOI: 10.1083/jcb.150.6.1385
Source: PubMed

ABSTRACT The syntrophins are a family of structurally related proteins that contain multiple protein interaction motifs. Syntrophins associate directly with dystrophin, the product of the Duchenne muscular dystrophy locus, and its homologues. We have generated alpha-syntrophin null mice by targeted gene disruption to test the function of this association. The alpha-Syn(-/)- mice show no evidence of myopathy, despite reduced levels of alpha-dystrobrevin-2. Neuronal nitric oxide synthase, a component of the dystrophin protein complex, is absent from the sarcolemma of the alpha-Syn(-/)- mice, even where other syntrophin isoforms are present. alpha-Syn(-/)- neuromuscular junctions have undetectable levels of postsynaptic utrophin and reduced levels of acetylcholine receptor and acetylcholinesterase. The mutant junctions have shallow nerve gutters, abnormal distributions of acetylcholine receptors, and postjunctional folds that are generally less organized and have fewer openings to the synaptic cleft than controls. Thus, alpha-syntrophin has an important role in synapse formation and in the organization of utrophin, acetylcholine receptor, and acetylcholinesterase at the neuromuscular synapse.

Download full-text


Available from: Stan Froehner, Sep 28, 2015
9 Reads
  • Source
    • "Similarly, the absence of associated proteins can cause changes in structure, and without exception, the motor endplate is noticeably disrupted in patients with DMD and mdx mice (Kong and Anderson, 1999; Adams et al., 2000; Marques et al., 2004; Banks et al., 2009; Chipman et al., 2010; Kulakowski et al., 2011). Patients with DMD and mdx mice also have increased susceptibility to injury compared to their non-dystrophic counterparts. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease in which weakness, increased susceptibility to muscle injury, and inadequate repair appear to underlie the pathology. While most attention has focused within the muscle fiber, we recently demonstrated in mdx mice (murine model for DMD) significant morphologic alterations at the motor endplate of the neuromuscular junction (NMJ) and corresponding NMJ transmission failure after injury. Here we extend these initial observations at the motor endplate to gain insight into the pre-vs. postsynaptic morphology, as well as the subsynaptic nuclei in healthy (WT) vs. mdx mice. We quantified the discontinuity and branching of the terminal nerve in adult mice. We report mdx-and age-dependent changes for discontinuity and an increase in branching when compared to WT. To examine mdx-and age-dependent changes in the relative localization of pre-and postsynaptic structures, we calculated NMJ occupancy, defined as the ratio of the footprint occupied by presynaptic vesicles vs. that of the underlying motor endplate. The normally congruent coupling between presynaptic and postsynaptic morphology was altered in mdx mice, independent of age. Finally we found an almost twofold increase in the number of nuclei and an increase in density (nuclei/area) underlying the NMJ. These outcomes suggest substantial remodeling of the NMJ during dystrophic progression. This remodeling reflects plasticity in both pre-and postsynaptic contributors to NMJ structure, and thus perhaps also NM transmission and muscle function.
    Frontiers in Physiology 09/2015; 6(252). DOI:10.3389/fphys.2015.00252 · 3.53 Impact Factor
  • Source
    • "The PDZ domain of α1-syntrophin binds to a variety of signaling molecules including sodium channels [21], [22], neuronal nitric oxide synthase [23]–[25], aquaporin-4 [26], [27] and serine/threonine kinases [28], [29]. Mice lacking α1-syntrophin display aberrations in neuromuscular synapses with undetectable levels of postsynaptic utrophin and reduced levels of acetylcholine receptor and acetylcholinesterase [30]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Microtubule-associated proteins of the MAP1 family (MAP1A, MAP1B, and MAP1S) share, among other features, a highly conserved COOH-terminal domain approximately 125 amino acids in length. We conducted a yeast 2-hybrid screen to search for proteins interacting with this domain and identified α1-syntrophin, a member of a multigene family of adapter proteins involved in signal transduction. We further demonstrate that the interaction between the conserved COOH-terminal 125-amino acid domain (which is located in the light chains of MAP1A, MAP1B, and MAP1S) and α1-syntrophin is direct and occurs through the pleckstrin homology domain 2 (PH2) and the postsynaptic density protein 95/disk large/zonula occludens-1 protein homology domain (PDZ) of α1-syntrophin. We confirmed the interaction of MAP1B and α1-syntrophin by co-localization of the two proteins in transfected cells and by co-immunoprecipitation experiments from mouse brain. In addition, we show that MAP1B and α1-syntrophin partially co-localize in Schwann cells of the murine sciatic nerve during postnatal development and in the adult. However, intracellular localization of α1-syntrophin and other Schwann cell proteins such as ezrin and dystrophin-related protein 2 (DRP2) and the localization of the axonal node of Ranvier-associated protein Caspr1/paranodin were not affected in MAP1B null mice. Our findings add to a growing body of evidence that classical MAPs are likely to be involved in signal transduction not only by directly modulating microtubule function, but also through their interaction with signal transduction proteins.
    PLoS ONE 11/2012; 7(11):e49722. DOI:10.1371/journal.pone.0049722 · 3.23 Impact Factor
  • Source
    • "Hindlimb suspension (unloading) causes muscle atrophy, delocalization, and posttranscriptional downregulation of nNOSμ protein to approximately 50% of wild-type levels (Tidball et al. 1998; Suzuki et al. 2007). Full nNOSμ expression requires its localization at the sarcolemma (Adams et al. 2000). Suzuki et al. (2007) reported that cytosolic nNOS activity is increased by unknown mechanisms and promotes hindlimb muscle atrophy through the activation of the forkhead transcription factor FoxO3 pathway (Figure 1). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuronal nitric oxide synthases (nNOS) are Ca2+/calmodulin-activated enzymes that synthesize the gaseous messenger nitric oxide (NO). nNOSμ and the recently described nNOSβ, both spliced nNOS isoforms, are important enzymatic sources of NO in skeletal muscle, a tissue long considered to be a paradigmatic system for studying NO-dependent redox signaling. nNOS is indispensable for skeletal muscle integrity and contractile performance, and deregulation of nNOSμ signaling is a common pathogenic feature of many neuromuscular diseases. Recent evidence suggests that both nNOSμ and nNOSβ regulate skeletal muscle size, strength, and fatigue resistance, making them important players in exercise performance. nNOSμ acts as an activity sensor and appears to assist skeletal muscle adaptation to new functional demands, particularly those of endurance exercise. Prolonged inactivity leads to nNOS-mediated muscle atrophy through a FoxO-dependent pathway. nNOS also plays a role in modulating exercise performance in neuromuscular disease. In the mdx mouse model of Duchenne muscular dystrophy, defective nNOS signaling is thought to restrict contractile capacity of working muscle in two ways: loss of sarcolemmal nNOSμ causes excessive ischemic damage while residual cytosolic nNOSμ contributes to hypernitrosylation of the ryanodine receptor, causing pathogenic Ca2+ leak. This defect in Ca2+ handling promotes muscle damage, weakness, and fatigue. This review addresses these recent advances in the understanding of nNOS-dependent redox regulation of skeletal muscle function and exercise performance under physiological and neuromuscular disease conditions.
    Biophysical Reviews 12/2011; 3(4). DOI:10.1007/s12551-011-0060-9
Show more