title: Reducing synuclein accumulation improves neuronal survival after spinal cord injury.
abstract: Spinal cord injury causes neuronal death, limiting subsequent regeneration and recovery. Thus, there is a need to develop strategies for improving neuronal survival after injury. Relative to our understanding of axon regeneration, comparatively little is known about the mechanisms that promote the survival of damaged neurons. To address this, we took advantage of lamprey giant reticulospinal neurons whose large size permits detailed examination of post-injury molecular responses at the level of individual, identified cells. We report here that spinal cord injury caused a select subset of giant reticulospinal neurons to accumulate synuclein, a synaptic vesicle-associated protein best known for its atypical aggregation and causal role in neurodegeneration in Parkinson's and other diseases. Post-injury synuclein accumulation took the form of punctate aggregates throughout the somata and occurred selectively in dying neurons, but not in those that survived. In contrast, another synaptic vesicle protein, synaptotagmin, did not accumulate in response to injury. We further show that the post-injury synuclein accumulation was greatly attenuated after single dose application of either the "molecular tweezer" inhibitor, CLR01, or a translation-blocking synuclein morpholino. Consequently, reduction of synuclein accumulation not only improved neuronal survival, but also increased the number of axons in the spinal cord proximal and distal to the lesion. This study is the first to reveal that reducing synuclein accumulation is a novel strategy for improving neuronal survival after spinal cord injury.
authors: Marine Biological Laboratory, The Eugene Bell Center for Regenerative Biology and Tissue Engineering, Woods Hole, MA 02543, United States.
authors: Stephanie M
authors: SM
authors: Fogerson
authors: Marine Biological Laboratory, The Eugene Bell Center for Regenerative Biology and Tissue Engineering, Woods Hole, MA 02543, United States; Section of Molecular Cell and Developmental Biology, The University of Texas at Austin, Austin, TX 78712, United States.
authors: Alexandra J
authors: AJ
authors: van Brummen
authors: Section of Molecular Cell and Developmental Biology, The University of Texas at Austin, Austin, TX 78712, United States.
authors: David J
authors: DJ
authors: Busch
authors: Marine Biological Laboratory, The Eugene Bell Center for Regenerative Biology and Tissue Engineering, Woods Hole, MA 02543, United States.
authors: Scott R
authors: SR
authors: Allen
authors: Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States.
authors: Robin
authors: R
authors: Roychaudhuri
authors: Marine Biological Laboratory, The Eugene Bell Center for Regenerative Biology and Tissue Engineering, Woods Hole, MA 02543, United States.
authors: Susan M L
authors: SM
authors: Banks
authors: Institute of Organic Chemistry, University of Duisburg-Essen, Essen 45117, Germany.
authors: Frank-Gerrit
authors: FG
authors: Klärner
authors: Institute of Organic Chemistry, University of Duisburg-Essen, Essen 45117, Germany.
authors: Thomas
authors: T
authors: Schrader
authors: Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States; Brain Research Institute and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA 90095, United States.
authors: Gal
authors: G
authors: Bitan
authors: Marine Biological Laboratory, The Eugene Bell Center for Regenerative Biology and Tissue Engineering, Woods Hole, MA 02543, United States. Electronic address: jmorgan@mbl.edu.
authors: Jennifer R
authors: JR
authors: Morgan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001952:Bridged-Ring Compounds / Q000627:therapeutic use; D002452:Cell Count; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007798:Lampreys; D007814:Larva; D060172:Morpholinos / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010755:Organophosphates / Q000627:therapeutic use; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D051843:Synucleins / Q000378:metabolism*
chemical_list: D001952:Bridged-Ring Compounds; C583031:CLR01 compound; D060172:Morpholinos; D010755:Organophosphates; D051843:Synucleins
keywords: CLR01; Lamprey; Molecular tweezer; Neurodegeneration; Parkinson's disease; Synaptotagmin