23
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Self-propelling vesicles define glycolysis as the minimal energy machinery for neuronal transport

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) facilitates fast axonal transport in neurons. However, given that GAPDH does not produce ATP, it is unclear whether glycolysis per se is sufficient to propel vesicles. Although many proteins regulating transport have been identified, the molecular composition of transported vesicles in neurons has yet to be fully elucidated. Here we selectively enrich motile vesicles and perform quantitative proteomic analysis. In addition to the expected molecular motors and vesicular proteins, we find an enrichment of all the glycolytic enzymes. Using biochemical approaches and super-resolution microscopy, we observe that most glycolytic enzymes are selectively associated with vesicles and facilitate transport of vesicles in neurons. Finally, we provide evidence that mouse brain vesicles produce ATP from ADP and glucose, and display movement in a reconstituted in vitro transport assay of native vesicles. We conclude that transport of vesicles along microtubules can be autonomous.

          Abstract

          How neurons produce energy to fuel fast axonal transport is only partially understood. Authors here report that most glycolytic enzymes are enriched in motile vesicles, and such glycolytic machinery can produce ATP autonomously to propel vesicle movement along microtubules in a cell-free assay.

          Related collections

          Most cited references33

          • Record: found
          • Abstract: found
          • Article: not found

          Vesicular glycolysis provides on-board energy for fast axonal transport.

          Fast axonal transport (FAT) requires consistent energy over long distances to fuel the molecular motors that transport vesicles. We demonstrate that glycolysis provides ATP for the FAT of vesicles. Although inhibiting ATP production from mitochondria did not affect vesicles motility, pharmacological or genetic inhibition of the glycolytic enzyme GAPDH reduced transport in cultured neurons and in Drosophila larvae. GAPDH localizes on vesicles via a huntingtin-dependent mechanism and is transported on fast-moving vesicles within axons. Purified motile vesicles showed GAPDH enzymatic activity and produced ATP. Finally, we show that vesicular GAPDH is necessary and sufficient to provide on-board energy for fast vesicular transport. Although detaching GAPDH from vesicles reduced transport, targeting GAPDH to vesicles was sufficient to promote FAT in GAPDH deficient neurons. This specifically localized glycolytic machinery may supply constant energy, independent of mitochondria, for the processive movement of vesicles over long distances in axons. Copyright © 2013 Elsevier Inc. All rights reserved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.

            The genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered γ-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD.
              Bookmark
              • Record: found
              • Abstract: not found
              • Article: not found

              Localization of the primary metabolic block produced by 2-deoxyglucose.

                Bookmark

                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                24 October 2016
                2016
                : 7
                : 13233
                Affiliations
                [1 ]Institut Curie , F-91405 Orsay, France
                [2 ]CNRS, UMR3306 , F-91405 Orsay, France
                [3 ]Inserm, U1005 , F-91405 Orsay, France
                [4 ]Faculté de Médecine, Univ. Paris Sud11 , F-94276 Le Kremlin-Bicêtre, France
                [5 ]Grenoble Institut des Neurosciences, GIN, Univ. Grenoble Alpes , F-38000 Grenoble, France
                [6 ]Inserm, U1216 , F-38000 Grenoble, France
                [7 ]Biotechnology Center, Technische Universität Dresden , D-01307 Dresden, Germany
                [8 ]CNRS, UMR 5297 , F-33000 Bordeaux, France
                [9 ]Interdisciplinary Institute for Neuroscience, IINS, Univ. Bordeaux , F-33077 Bordeaux, France
                [10 ]CHU Grenoble Alpes , F-38000 Grenoble, France
                Author notes
                [*]

                These authors contributed equally to this work

                [†]

                Present address: IGBMC, CNRS UMR 7104—Inserm U964, F-67404 Illkirch-Graffenstaden, France

                [‡]

                Present address: ESPCI-ParisTech, PSL Research University, F-75005 Paris, France and CNRS, UMR8249, F-75005 Paris, France

                Article
                ncomms13233
                10.1038/ncomms13233
                5078996
                27775035
                6d1a1540-205f-4524-9da5-6433861da2e5
                Copyright © 2016, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 21 April 2016
                : 14 September 2016
                Categories
                Article

                Uncategorized
                Uncategorized

                Comments

                Comment on this article