Absence of α-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin

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 α-syntrophin null mice by targeted gene disruption to test the function of this association. The α-Syn(-/-) mice show no evidence of myopathy, despite reduced levels of α-dystrobrevin-2. Neuronal nitric oxide synthase, a component of the dystrophin protein complex, is absent from the sarcolemma of the α-Syn(-/-) mice, even where other syntrophin isoforms are present. α-Syn(-/-) neuromuscular junctions have undetectable levels of postsynapticutrophin 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, α-syntrophin has an important role in synapse formation and in the organization of utrophin, acetylcholine receptor, and acetylcholinesterase at the neuromuscular synapse.