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      Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human G M1-Gangliosidosis


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          G M1-gangliosidosis is caused by a reduced activity of β-galactosidase ( Glb1), resulting in intralysosomal accumulations of G M1. The aim of this study was to reveal the pathogenic mechanisms of G M1-gangliosidosis in a new Glb1 knockout mouse model. Glb1 −/− mice were analyzed clinically, histologically, immunohistochemically, electrophysiologically and biochemically. Morphological lesions in the central nervous system were already observed in two-month-old mice, whereas functional deficits, including ataxia and tremor, did not start before 3.5-months of age. This was most likely due to a reduced membrane resistance as a compensatory mechanism. Swollen neurons exhibited intralysosomal storage of lipids extending into axons and amyloid precursor protein positive spheroids. Additionally, axons showed a higher kinesin and lower dynein immunoreactivity compared to wildtype controls. Glb1 −/− mice also demonstrated loss of phosphorylated neurofilament positive axons and a mild increase in non-phosphorylated neurofilament positive axons. Moreover, marked astrogliosis and microgliosis were found, but no demyelination. In addition to the main storage material G M1, G A1, sphingomyelin, phosphatidylcholine and phosphatidylserine were elevated in the brain. In summary, the current Glb1 −/− mice exhibit a so far undescribed axonopathy and a reduced membrane resistance to compensate the functional effects of structural changes. They can be used for detailed examinations of axon–glial interactions and therapy trials of lysosomal storage diseases.

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          Kinesin superfamily motor proteins and intracellular transport.

          Intracellular transport is fundamental for cellular function, survival and morphogenesis. Kinesin superfamily proteins (also known as KIFs) are important molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs. The mechanisms by which different kinesins recognize and bind to specific cargos, as well as how kinesins unload cargo and determine the direction of transport, have now been identified. Furthermore, recent molecular genetic experiments have uncovered important and unexpected roles for kinesins in the regulation of such physiological processes as higher brain function, tumour suppression and developmental patterning. These findings open exciting new areas of kinesin research.
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            Intracellular transport and kinesin superfamily proteins, KIFs: structure, function, and dynamics.

            Various molecular cell biology and molecular genetic approaches have indicated significant roles for kinesin superfamily proteins (KIFs) in intracellular transport and have shown that they are critical for cellular morphogenesis, functioning, and survival. KIFs not only transport various membrane organelles, protein complexes, and mRNAs for the maintenance of basic cellular activity, but also play significant roles for various mechanisms fundamental for life, such as brain wiring, higher brain functions such as memory and learning and activity-dependent neuronal survival during brain development, and for the determination of important developmental processes such as left-right asymmetry formation and suppression of tumorigenesis. Accumulating data have revealed a molecular mechanism of cargo recognition involving scaffolding or adaptor protein complexes. Intramolecular folding and phosphorylation also regulate the binding activity of motor proteins. New techniques using molecular biophysics, cryoelectron microscopy, and X-ray crystallography have detected structural changes in motor proteins, synchronized with ATP hydrolysis cycles, leading to the development of independent models of monomer and dimer motors for processive movement along microtubules.
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              Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability.

              Cholesterol/sphingolipid microdomains (lipid rafts) in the membrane are involved in protein trafficking, formation of signaling complexes, and regulation of actin cytoskeleton. Here, we show that lipid rafts exist abundantly in dendrites of cultured hippocampal neurons, in which they are associated with several postsynaptic proteins including surface AMPA receptors. Depletion of cholesterol/sphingolipid leads to instability of surface AMPA receptors and gradual loss of synapses (both inhibitory and excitatory) and dendritic spines. The remaining synapses and spines in raft-depleted neurons become greatly enlarged. The importance of lipid rafts for normal synapse density and morphology could explain why cholesterol promotes synapse maturation in retinal ganglion cells (Mauch et al., 2001) and offers a potential link between disordered cholesterol metabolism and the synapse loss seen in neurodegenerative disease.

                Author and article information

                J Clin Med
                J Clin Med
                Journal of Clinical Medicine
                02 April 2020
                April 2020
                : 9
                : 4
                : 1004
                [1 ]Department of Pathology, University of Veterinary Medicine Hannover, D-30559 Hannover, Germany; Deborah.Eikelberg@ 123456tiho-hannover.de (D.E.); Annika.Lehmbecker@ 123456tiho-hannover.de (A.L.); Witchaya.Tongtako@ 123456tiho-hannover.de (W.T.); Kerstin.Hahn@ 123456tiho-hannover.de (K.H.); Andre.Habierski@ 123456tiho-hannover.de (A.H.); Ingo.Gerhauser@ 123456tiho-hannover.de (I.G.)
                [2 ]Department of Physiological Chemistry, University of Veterinary Medicine Hannover, D-30559 Hannover, Germany; Graham.Brogden@ 123456tiho-hannover.de (G.B.); Hassan.Naim@ 123456tiho-hannover.de (H.Y.N.)
                [3 ]c/o Faculty of Veterinary Science, Prince of Sonkla University, 5 Karnjanavanich Rd., Hat Yai, Songkhla 90110, Thailand
                [4 ]Villa Metabolica, University of Mainz, Langenbeckstraße 2, D-55131 Mainz, Germany; Julia.Hennermann@ 123456unimedizin-mainz.de
                [5 ]Department for Physiology and Cell Biology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; Felix.Felmy@ 123456tiho-hannover.de
                Author notes
                Author information
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                : 05 March 2020
                : 30 March 2020

                astrogliosis,axonopathy,β-galactosidase deficiency,electrophysiology,gm1-gangliosidosis,knockout mouse model,lipid analysis,microgliosis,neuronal vacuolation


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