Brain proteomic studies

There is now a growing interest in proteomic studies of brain synapses. Recent studies have revealed a high molecular complexity in the pre- and postsynaptic areas, with thousands of proteins [6]. An important investigation for the future is to identify posttranslational modifications, miscoded as well as misfolded proteins, likely to have an impact on different aspects of synaptic function as a response to the environment as well as to the lifestyle. The first challenge is to identify and quantify the presence and variation of different proteins in key structures of the pre- and postsynaptic areas in order to relate protein structures to synaptic function. Recently, a new model has been presented describing the molecular complexity of the synapse with important aspects in emotions, thinking, memory, and consciousness [7] (Fig. 17.2). 

Mass spectrometry has been applied mainly in proteome research, but also in discovery and quantitation of neuropeptides that are involved in pain mechanisms, such as nocistatin, substance P, or verification of, for example, the structure of endogenous morphine in the central nervous system. Some proteomics studies of pain are aimed at the search for pain markers in cerebrospinal fluid, as it may reflect changes in brain and spinal cord functioning. Another research area concerns proteome analysis in cancer pain using spinal cord tissue and animal models. 

Puchades, M., Hansson, S.F., Nilsson, C.L., Andreassen, N., Blennow, K., Davidsson, P. (2003) Proteomic studies of potential cerebrospinal fliud protein markers for Alzheimer s disease. Brain Res. Mol. Brain Res., 118, 140-146. 

Proteomics Studies of Traumatic Brain Injury Kevin K W. Wang, Andrew Ottens,... 

Such imbalanced antioxidant systems in schizophrenia could lead to oxidative stress- and ROS-mediated injury as supported by increased lipid peroxidation products and reduced membrane polyunsaturated fatty acids (PUFAs). Decrease in membrane phospholipids in blood cells of psychotic patients (Keshavan et al., 1993 Reddy et al., 2004) and fibroblasts from drug-naive patients (Mahadik et al., 1994) as well as in postmortem brains (Horrobin et al., 1991) have indeed been reported. It has also been suggested that peripheral membrane anomalies correlate with abnormal central phospholipid metabolism in first-episode and chronic schizophrenia patients (Pettegrewet al., 1991 Yao et al., 2002). Recently, a microarray and proteomic study on postmortem brain showed anomalies of mitochondrial function and oxidative stress pathways in schizophrenia (Prabakaran et al., 2004). Mitochondrial dysfunction in schizophrenia has also been observed by Ben-Shachar (2002) and Altar et al. (2005). As main ROS producers, mitochondria are particularly susceptible to oxidative damage. Thus, a deficit in glutathione (GSH) or immobilization stress induce greater increase in lipid peroxidation and protein oxidation in mitochondrial rather than in cytosolic fractions of cerebral cortex (Liu et al., 1996). 

Stephan, C., Hamacher, M., Meyer, H. E. (2005). 3rd HUPO Brain Proteome Project Workshop promises successful pilot studies. Proteomics 5, 615-616. 

This study is part of the German Research Network on Demenha and was fimded by the German Federal Ministry of Educahon and Research (grant 01 G1 0102). JW and PL are supported by BMBF-funded project NGFN2 (Sub-project No. PPO-SIOTIO), and are members of the Human Brain Proteome Project of the Human Proteome Organisahon (HUPO). 

Many of the methods described in the previous section have been applied to the study of multiprotein complexes in the nervous system. The first proteomic study of a neurotransmitter receptor complex in 2000 (Husi et al. 2000) has been followed by similar studies of important classes of brain receptors and channels (Table 1). As shown in Table 1, complexes associated with ion channels such as members of the ionotropic class of glutamate receptors and GPCRs such as the metabotropic class of glutamate receptors have been described. Here we review a number of such complexes and discuss how their components relate to nervous system biology. 

The protein systems used in these chromaffin vesicles, which represent dense core secretory vesicles (71), resemble those of brain synaptic vesicles (88) and secretory vesicles in the liver (89). Proteomic studies provide inference for secretory vesicle protein systems used for functions of these vesicles, including their biogenesis, that are required for production of enkephalin and related neuropeptides in brain and endocrine tissues. 

Secretory vesicles at synaptic nerve terminals in the brain are essential for chemical neurotransmission among neurons. Proteomic studies of synaptic proteins have revealed their regulation by brain injury (90), brain-derived neurotrophic factor (BDNF) (91), and drug regulation by morphine (92). The protein systems that support secretory vesicle exocytosis of peptide neurotransmitters and receptor activation at synaptic junctions of neurons function in concert to achieve neuropeptide-mediated communication in neural circuits. 

Proteomic studies of the brain pose significant challenges. Brain tissue collection, dissection, preservation, biochemical and molecular integrity are all critical aspects of neuropro-... 

Fiorini A, Sultana R, Forster S, Perluigi M, Cenini G, Cini C et al (2013) Antisense directed against PS-1 gene decreases brain oxidative markers in aged senescence accelerated mice (SAMP8) and reverses learning and memory impairment A proteomics study. Free Radic Biol Med 65 1-14... 

A niunber of brain region proteomes have been studied to investigate differences in protein expression. Preliminary analysis of the mouse cerebellar proteome has identified 30 proteins (Beranova-Giorgianni, Giorgianni et al. 2002) and analysis of the porcine cerebellum led to identification of 56 spots (Friso and Wikstrom 1999). A developmental proteomic study of the rat cerebellum yielded resolution of over 3000 spots and identification of 67 of these (Taoka, Wakamiya et al. 2000). Most proteins showed an increase in abundance as the cerebellum matured, however, 42 spots appeared to be exclusively expressed in the immature cerebellum. Some of the latter were identified by MS and included proteins with defined roles in nervous system development. 

Fig. 3.13. imaging LA-ICP-MS combined with proteome studies on selected part of brain tissue (hippocampus). 

The rapid progress in proteomics and peptidomics during the last decade offers us new possibilities to study clinical aspects of disorders and diseases related to the brain [1], These strategies also offer new tools to follow chemical modifications and altered metabolic disturbances that may be indicative of pathophysiological adaptations related to environmental and psychosocial prolonged stress. These techniques can contribute to developments in the diagnostic and therapeutic fields of psychiatric... 

Marcotte ER, Srivastava LK, Quirion R. 2003. cDNA microarray and proteomic approaches in the study of brain diseases focus on schizophrenia and Alzheimer s disease. Pharmacol Ther 100 63. 

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