Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease, characterized by the lack of the large cytoskeletal protein dystrophin (Dp427) in skeletal muscles and other cell types. Shorter dystrophin isoforms, also exist, expressed in a tissue-specific manner and often substituting Dp427. In the peripheral nervous system (PNS), Schwann cells (SCs), which are responsible for axon myelination, express the Dp116 isoform, which binds to the same large glycoprotein complex that in muscles connects actin, Dp427 and extracellular matrix. Central core of this complex are alpha- and beta-dystroglycan (DG). In SCs, the Dp116-DG complex (DGC) confers myelin integrity and preservation of nerve fiber conduction properties. To date, little is known on the effects that DMD has on peripheral sensory-motor nerves. Our previous studies on the sciatic nerves of wild-type and mdx mice, a model of DMD lacking the sole Dp427, highlighted a significant reduction in the GABAergic signaling system of dystrophic mice between SCs and axons, as well as Abeta- mechanoreceptor fiber excitability. Therefore, considering the role of Dp116-DGC in myelin, we analyzed whether protein levels and immunolocalization of three major complex components: alpha- and beta-DG, and dystrobrevin, were affected. Levels, distribution and intensity of immunolabeling of all three proteins were significantly reduced in mdx mouse sciatic nerves compared to wild-type, confirming alteration of myelin integrity. Since the expression of Dp116 was not equally altered, we hypothesized as a possible cause activation of proinflammatory extracellular matrix metalloproteinases (MMP) 2 and 9, both having alpha and beta-DG among their targets. Indeed, gel zymography and Western immunoblot revealed a significant induction of MMP2 activity in mdx mouse sciatic nerves compared to wild-type. This suggests that a DMD-induced DG cleavage within the myelin sheets could be the upstream cause of the Dp116-DGC degradation and of the SC-axon cross talk deregulation.
The counter effect of DMD in peripheral innervation: alterations of the dystrophin-dystroglycan complex in the sciatic nerve of dystrophic mdx mice / Di Nuzzo, S.; Soligo, M.; Manni, L.; Ferretti, V.; De Stefano, M. E.. - (2023). (Intervento presentato al convegno Società italiana di Neuroscienze tenutosi a Torino, Italia).
The counter effect of DMD in peripheral innervation: alterations of the dystrophin-dystroglycan complex in the sciatic nerve of dystrophic mdx mice
Di Nuzzo S.;Soligo M.;Ferretti V.;De Stefano M. E.
2023
Abstract
Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease, characterized by the lack of the large cytoskeletal protein dystrophin (Dp427) in skeletal muscles and other cell types. Shorter dystrophin isoforms, also exist, expressed in a tissue-specific manner and often substituting Dp427. In the peripheral nervous system (PNS), Schwann cells (SCs), which are responsible for axon myelination, express the Dp116 isoform, which binds to the same large glycoprotein complex that in muscles connects actin, Dp427 and extracellular matrix. Central core of this complex are alpha- and beta-dystroglycan (DG). In SCs, the Dp116-DG complex (DGC) confers myelin integrity and preservation of nerve fiber conduction properties. To date, little is known on the effects that DMD has on peripheral sensory-motor nerves. Our previous studies on the sciatic nerves of wild-type and mdx mice, a model of DMD lacking the sole Dp427, highlighted a significant reduction in the GABAergic signaling system of dystrophic mice between SCs and axons, as well as Abeta- mechanoreceptor fiber excitability. Therefore, considering the role of Dp116-DGC in myelin, we analyzed whether protein levels and immunolocalization of three major complex components: alpha- and beta-DG, and dystrobrevin, were affected. Levels, distribution and intensity of immunolabeling of all three proteins were significantly reduced in mdx mouse sciatic nerves compared to wild-type, confirming alteration of myelin integrity. Since the expression of Dp116 was not equally altered, we hypothesized as a possible cause activation of proinflammatory extracellular matrix metalloproteinases (MMP) 2 and 9, both having alpha and beta-DG among their targets. Indeed, gel zymography and Western immunoblot revealed a significant induction of MMP2 activity in mdx mouse sciatic nerves compared to wild-type. This suggests that a DMD-induced DG cleavage within the myelin sheets could be the upstream cause of the Dp116-DGC degradation and of the SC-axon cross talk deregulation.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
