Abstract
Duchenne muscular dystrophy is the most frequently inherited neuromuscular disease of childhood, and is characterised by primary abnormalities in the Dmd gene encoding the membrane cytoskeletal protein dystrophin. Aside from the well-established skeletal muscle degeneration and cardio-respiratory complications, extra-muscular manifestations are also evident. Comparative label-free liquid chromatography mass spectrometric analyses of brain tissue and serum derived from the mdx-4cv animal model of the disease have identified novel proteomic markers of astrogliosis and inflammation respectively. The elucidation of proteome-wide changes in the mdx-4cv dystrophin-deficient brain revealed alterations in proteins involved in cytoskeletal stabilisation, calcium homeostasis, metabolism and reactive gliosis. Elevated abundance of some brain-associated proteins were also detected in serum samples, suggesting that the presence of brain-derived proteins in serum could potentially reflect the extent of dystrophinopathy in the brain. A large number of differentially abundant proteins in immunodepleted mdx-4cv serum were also identified by label-free mass spectrometry. In particular these proteins were associated with chronic tissue damage, necrosis and sterile inflammation. A variety of these potential circulatory biomarkers linked to muscular dystrophy were validated independently by comparative immunoblot analysis and enzyme-linked immunosorbent assays. Further research will be required to investigate whether such protein biomarkers are passively leaked or actively secreted into the circulatory system. These novel protein marker candidates identified by proteomic profiling of brain tissue and serum offer insights into the pathophysiology of dystrophinopathy and may be further investigated for their potential use in the diagnosis, prognosis and therapeutic monitoring of Duchenne muscular dystrophy.
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