Neuroproteomics: How Many Angels can be Identified in an Extract from the Head of a Pin?

Abstract

Oscar Wilde once defined fox hunting as an activity of “the unspeakable in pursuit of the uneatable.” This sentiment may well reflect the reaction of some mass spectrometry laboratories to neuroscience colleagues rushing in with a vial containing a hopelessly inadequate amount of sample originating from a tissue of intractable complexity, or in other words a neuroproteomics project. This issue of Molecular and Cellular Proteomics focuses on application of proteomics to current problems in neuroscience. Although some neuroscientists have ventured into proteomics, most of the neuroscience community has yet to embrace proteomics approaches. Despite increasing interest and awareness of the potential of such approaches (1, 2), many neuroscientists are still in the early stages of a learning curve on how proteomics approaches can be leveraged for new insights and knowledge in their field. Conversely, many proteomics laboratories are not aware of the daunting complexity and limited quantities of samples derived from neural tissues. The review and commentary papers presented in this issue highlight current issues in neuroscience that may now be ready for interrogation by modern proteomics approaches. The primary research papers in this issue provide examples of success in overcoming the many hurdles of neuroproteomics projects, and the exciting new insights that such achievements bring. Despite advances in sensitivity in mass spectrometry (MS), protein yield from neural tissues is often a harsh limiting factor when considering the quantities needed for proteomics. Both the central and peripheral nervous systems (CNS 1 and PNS, respectively) are composed of mixtures of different cell types with intricate architecture and connectivity, presenting major sampling and analysis challenges. These challenges typically require separation of different cell types prior to proteomics, thereby further limiting sample size, or trying to infer cell-type specific changes from tissue lysates. The cover of this issue shows an example of such cellular complexity, illustrating the composition of the mammalian retina with photoreceptors, glia, and neurons assembled into complex layers that are essential for vision. The intricate cytoplasmic extensions of the glial and neuronal cells within the retina, and the axonal extensions from the retina to the brain, add additional layers of complexity that are not depicted in the image. This juxtaposition of different cell types and subtypes, and the intertwined cytoplasmic processes of neurons and glial cells, presents a daunting challenge for proteomics of different neuronal and glial cell types. The work by Grosche et al. (3) in this issue tackled the complexity of the retina with a unique fractionation approach tailored to isolate and dissect the proteome of the Mueller glial cells, a specialized glial cell population unique to the retina. Quantitative mass spectrometry on Muller cell enriched versus depleted fractions enabled the authors to identify specific functions of this glial population in the retina.