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New findings in rodents and human brain shed light on the mechanisms of major depressive disorder (MDD), uncovering over-expression of MKP-1 (mitogen-activated protein kinase [MAPK] phosphatase-1)...and identifying a new therapeutic target. MKP-1, also known as dual-specificity phosphatase-1 (DUSP1), is a member of a family of proteins that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of the MAPK cascade4, a major signaling pathway involved in neuronal plasticity, function and survival This study identifies MKP-1 as a key factor in MDD pathophysiology, and as a new target for therapeutic interventions.f Here we use whole-genome expression profiling of postmortem tissue and show significantly increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1, encoded by DUSP1, but hereafter called MKP-1) in the hippocampal subfields of subjects with MDD compared to matched controls. MKP-1, also known as dual-specificity phosphatase-1 (DUSP1), is a member of a family of proteins that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of the MAPK cascade4, a major signaling pathway involved in neuronal plasticity, function and survival. We tested the role of altered MKP-1 expression in rat and mouse models of depression and found that increased hippocampal MKP-1 expression, as a result of stress or viral-mediated gene transfer, causes depressive behaviors. Conversely, chronic antidepressant treatment normalizes stress-induced MKP-1 expression and behavior, and mice lacking MKP-1 are resilient to stress. These postmortem and preclinical studies identify MKP-1 as a key factor in MDD pathophysiology and as a new target for therapeutic interventions.

Study provides the first evidence of a direct relationship between the depression of protein synthesis in skeletal muscle by PIF and Ang II, through activation of PKR, and eIF2{alpha} phosphorylation, and the enhanced degradation of the myofibrillar protein myosin, through activation of NF-{kappa}B resulting in an increased expression and activity of the ubiquitin-proteasome proteolytic pathway. This suggests that agents that target PKR may be effective in the treatment of muscle atrophy in cancer cachexia or other wasting conditions.

Jonathan D. Smith, Department of Cell Biology, NC10, Cleveland Clinic, 9500 Euclid Avenue, Cleveland OH 44195. E-mail smithj4@ccf.org -----     -----     -----     ----- HDL-cholesterol is the "good cholesterol" because of its reverse cholesterol transport and antiinflammatory activities. However, HDL and apolipoprotein A-I can lose their protective activities through changes in protein or lipid composition as well as protein modifications. Assays for dysfunctional HDL could potentially be used as a criterion for preventative therapy.

Effect of a protein and energy dense n-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial

Eley, HL and Tisdale, MJ: Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham UK. January 2007

Skeletal Muscle Atrophy: Link between Depression of Protein Synthesis and Increase in Degradation -- Eley and Tisdale 282 (10): 7087 -- Journal of Biological Chemistry. Eley, HL and Tisdale, MJ: Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham UK. January 2007