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      SORLA-Mediated Trafficking of TrkB Enhances the Response of Neurons to BDNF

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          Abstract

          Stimulation of neurons with brain-derived neurotrophic factor (BDNF) results in robust induction of SORLA, an intracellular sorting receptor of the VPS10P domain receptor gene family. However, the relevance of SORLA for BDNF-induced neuronal responses has not previously been investigated. We now demonstrate that SORLA is a sorting factor for the tropomyosin-related kinase receptor B (TrkB) that facilitates trafficking of this BDNF receptor between synaptic plasma membranes, post-synaptic densities, and cell soma, a step critical for neuronal signal transduction. Loss of SORLA expression results in impaired neuritic transport of TrkB and in blunted response to BDNF in primary neurons; and it aggravates neuromotoric deficits caused by low BDNF activity in a mouse model of Huntington’s disease. Thus, our studies revealed a key role for SORLA in mediating BDNF trophic signaling by regulating the intracellular location of TrkB.

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          Most cited references19

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          Anterograde transport of brain-derived neurotrophic factor and its role in the brain.

          The role of neurotrophins as target-derived proteins that promote neuron survival following their retrograde transport from the terminals to the cell bodies of neurons has been firmly established in the developing peripheral nervous system. However, neurotrophins appear to have more diverse functions, particularly in the adult central nervous system. Brain-derived neurotrophic factor (BDNF), for example, produces a variety of neuromodulatory effects in the brain that are more consistent with local actions than with long-distance retrograde signalling. Here we show that BDNF is widely distributed in nerve terminals, even in brain areas such as the striatum that lack BDNF messenger RNA, and that inhibition of axonal transport or deafferentation depletes BDNF. The number of striatal neurons that contain the calcium-binding protein parvalbumin was decreased in BDNF+/- and BDNF-/- mice in direct proportion to the loss of BDNF protein, which is consistent with anterogradely supplied BDNF having a functional role in development or maintenance. Thus the anterograde transport of BDNF from neuron cell bodies to their terminals may be important for the trafficking of BDNF in the brain.
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            Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture.

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              A BDNF autocrine loop in adult sensory neurons prevents cell death.

              During the initial phase of their development, sensory neurons of the dorsal root ganglion (DRG) require target-derived trophic support for their survival, but as they mature they lose this requirement. Because many of these neurons express BDNF (brain-derived neurotrophic factor) messenger RNA, we hypothesized that BDNF might act as an autocrine survival factor in adult DRG neurons, thus explaining their lack of dependence on exogenous growth factors. When cultured adult DRG cells were treated with antisense oligonucleotides to BDNF, expression of BDNF protein was reduced by 80%, and neuronal survival was reduced by 35%. These neurons could be rescued by exogenous BDNF or neurotrophin-3, but not by other growth factors. Similar results were obtained with single-neuron microcultures, whereas microcultures derived from mutant mice lacking BDNF were unaffected by antisense oligonucleotides. Our results strongly support an autocrine role for BDNF in mediating the survival of a subpopulation of adult DRG neurons.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                19 August 2013
                : 8
                : 8
                : e72164
                Affiliations
                [1 ]Molecular Cardiovascular Research, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
                [2 ]Institute for Medical Genetics and Human Genetics, Charité - University Medicine Berlin, Berlin, Germany
                [3 ]Department of Biomedicine, Aarhus University, Aarhus, Denmark
                University of Louisville, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MR DH TEW. Performed the experiments: MR DH ANF. Analyzed the data: MR DH ANF. Contributed reagents/materials/analysis tools: JK. Wrote the paper: MR DH TEW.

                Article
                PONE-D-13-16383
                10.1371/journal.pone.0072164
                3747043
                23977241
                d86b10a5-6633-4b83-b127-8aae0088472c
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 21 April 2013
                : 7 July 2013
                Page count
                Pages: 8
                Funding
                Funding was provided by: http://www.brightfocus.org/; http://www.fritz-thyssen-stiftung.de/; http://www.carlsberggroup.com/Company/Foundations/Pages/default.aspx; and http://www.dfg.de/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Genetics
                Human Genetics
                Autosomal Dominant
                Huntington Disease
                Model Organisms
                Animal Models
                Mouse
                Molecular Cell Biology
                Signal Transduction
                Signaling Cascades
                Signaling Pathways
                Membranes and Sorting
                Neuroscience
                Behavioral Neuroscience
                Cellular Neuroscience
                Molecular Neuroscience
                Neurobiology of Disease and Regeneration
                Proteomics

                Uncategorized
                Uncategorized

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