Quantitative and Integrative Proteome Analysis of Peripheral Nerve Myelin Identifies Novel Myelin Proteins and Candidate Neuropathy Loci
2011
Peripheral nerve
myelinfacilitates rapid impulse conduction and normal motor and sensory functions. Many aspects of
myelin
biogenesis, glia–axonal interactions, and nerve homeostasis are poorly understood at the molecular level. We therefore hypothesized that only a fraction of all relevant
myelinproteins has been identified so far. Combining gel-based and gel-free proteomic approaches, we identified 545 proteins in purified mouse sciatic nerve
myelin, including 36 previously known
myelinconstituents. By mass spectrometric quantification, the predominant P0, periaxin, and
myelin basic proteinconstitute 21, 16, and 8% of the total
myelinprotein, respectively, suggesting that their relative abundance was previously misestimated due to technical limitations regarding protein separation and visualization. Focusing on tetraspan-transmembrane proteins, we validated novel
myelinconstituents using immuno-based methods. Bioinformatic comparison with mRNA-abundance profiles allowed the categorization in functional groups coregulated during
myelin
biogenesisand maturation. By differential
myelinproteome analysis, we found that the abundance of
septin9, the protein affected in
hereditary neuralgic amyotrophy, is strongly increased in a novel mouse model of demyelinating neuropathy caused by the loss of prion protein. Finally, the systematic comparison of our
compendiumwith the positions of human disease loci allowed us to identify several candidate genes for hereditary demyelinating neuropathies. These results illustrate how the integration of unbiased proteome, transcriptome, and genome data can contribute to a molecular dissection of the
biogenesis, cell biology, metabolism, and pathology of
myelin.
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