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Proteomics is a promising approach, which provides information about the expression of proteins and increasingly finds application in life science and disease research. Meanwhile, proteomics has proven to be applicable even on post mortem human brain tissue and has opened a new area in neuroproteomics. Thereby, neuroproteomics is usually employed to generate large protein profiles of brain tissue, which mostly reflect the expression of highly abundant proteins. As a complementary approach, the focus on sub-proteomes would enhance more specific insight into brain function. Sub-proteomes are accessible via several strategies, including affinity pull-down approaches, immunoprecipitation or subcellular fractionation. The extraordinary potential of subcellular proteomics to reveal even minute differences in the protein constitution of related cellular organelles is exemplified by a recent global description of neuromelanin granules from the human brain, which could be identified as pigmented lysosome-related organelles.