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    ABSTRACT: Increased endoplasmic reticulum (ER) stress and the activated unfolded protein response (UPR) signaling associated with it play key roles in physiological processes as well as under pathological conditions. The UPR normally protects cells and re-establishes cellular homeostasis, but prolonged UPR activation can lead to the development of various pathologies. These features make the UPR signaling pathway an attractive target for the treatment of diseases whose pathogenesis is characterized by chronic activation of this pathway. Here, we focus on the molecular signaling pathways of the UPR and suggest possible ways to target this response for therapeutic purposes.
    Seminars in Immunopathology 04/2013; · 5.38 Impact Factor
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    ABSTRACT: Mitofusin 2 (MFN2) plays critical roles in both mitochondrial fusion and the establishment of mitochondria-endoplasmic reticulum (ER) interactions. Hypothalamic ER stress has emerged as a causative factor for the development of leptin resistance, but the underlying mechanisms are largely unknown. Here, we show that mitochondria-ER contacts in anorexigenic pro-opiomelanocortin (POMC) neurons in the hypothalamus are decreased in diet-induced obesity. POMC-specific ablation of Mfn2 resulted in loss of mitochondria-ER contacts, defective POMC processing, ER stress-induced leptin resistance, hyperphagia, reduced energy expenditure, and obesity. Pharmacological relieve of hypothalamic ER stress reversed these metabolic alterations. Our data establish MFN2 in POMC neurons as an essential regulator of systemic energy balance by fine-tuning the mitochondrial-ER axis homeostasis and function. This previously unrecognized role for MFN2 argues for a crucial involvement in mediating ER stress-induced leptin resistance.
    Cell 09/2013; 155(1):172-87. · 31.96 Impact Factor
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    ABSTRACT: Although the pathophysiology of neurodegenerative diseases is distinct for each disease, considerable evidence suggests that a single manipulation, dietary restriction, is strikingly protective against a wide range of such diseases. Thus pharmacological mimetics of dietary restrictions could prove widely protective across a range of neurodegenerative diseases. The PPAR transcription complex functions to re-program gene expression in response to nutritional deprivation as well as in response to a wide variety of lipophilic compounds. In mammals there are three PPAR homologs, which dimerize with RXR homologs and recruit coactivators Pgc1-alpha and Creb-binding protein (Cbp). PPARs are currently of clinical interest mainly because PPAR activators are approved for use in humans to reduce lipidemia and to improve glucose control in Type 2 diabetic patients. However, pharmacological enhancement of the activity of the PPAR complex is neuroprotective across a wide variety of models for neuropathological processes, including stroke, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Conversely activity of the PPAR transcriptional complex is reduced in a variety of neuropathological processes. The main mechanisms mediating the neuroprotective effects of the PPAR transcription complex appear to be re-routing metabolism away from glucose metabolism and toward alternative subtrates, and reduction in inflammatory processes. Recent evidence suggests that the PPAR transcriptional complex may also mediate protective effects of dietary restriction on neuropathological processes. Thus this complex represents one of the most promising for the development of pharmacological treatment of neurodegenerative diseases.
    Translational Neuroscience. 09/2012; 3(3).

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