Proteomic profiling of the brain from the <i>wobbler</i> mouse model of amyotrophic lateral sclerosis reveals elevated levels of the astrogliosis marker glial fibrillary acidic protein

Abstract

The wobbler mouse is a widely used model system of amyotrophic lateral sclerosis and exhibits progressive neurodegeneration and neuroinflammation in association with skeletal muscle wasting. This study has used wobbler brain preparations for the systematic and mass spectrometric determination of proteome-wide changes. The proteomic characterization of total protein extracts from wobbler specimens was carried out with the help of an Orbitrap mass spectrometer and revealed elevated levels of glia cell marker proteins, i.e., glial fibrillary acidic protein and the actin-binding protein coronin. In contrast, the abundance of the actin-binding protein neurabin and the scaffolding protein named piccolo of the presynaptic cytomatrix were shown to be reduced. The increased abundance of glial fibrillary acidic protein, which is frequently used in neuropathological studies as a marker protein of glial scar formation, was confirmed by immunoblotting. In analogy, the proteomic profiling of the brain from another established murine model of motor neuron disease, the SOD1mouse, also showed increased levels of this intermediate filament protein. This suggests that neurodegenerative processes are associated with astrogliosis in both the wobbler and SOD1 brain.

How Can Proteomics Help to Elucidate the Pathophysiological Crosstalk in Muscular Dystrophy and Associated Multi-System Dysfunction?

“…Thus, increased levels of GFAP in the mdx-4cv brain, which were demonstrated by proteomics, comparative immunoblotting and immunofluorescence microscopy [ 371 ], strongly suggest the presence of astrogliosis being part of the neurodegenerative process in DMD [ 34 ]. However, astrogliosis appears to be a frequent occurrence in the brain in response to general tissue damage [ 373 ], as was recently shown by the proteomic analysis of the wobbler mouse model of amyotrophic lateral sclerosis [ 376 ]. This reduces the diagnostic usefulness of GFAP as a specific biomarker of muscular dystrophy-related changes in the central nervous system but does not limit its general suitability as an astrogliosis marker protein.…”