title: AAV-mediated expression of BAG1 and ROCK2-shRNA promote neuronal survival and axonal sprouting in a rat model of rubrospinal tract injury.
abstract: A lesion to the rat rubrospinal tract is a model for traumatic spinal cord lesions and results in atrophy of the red nucleus neurons, axonal dieback, and locomotor deficits. In this study, we used adeno-associated virus (AAV)-mediated over-expression of BAG1 and ROCK2-shRNA in the red nucleus to trace [by co-expression of enhanced green fluorescent protein (EGFP)] and treat the rubrospinal tract after unilateral dorsal hemisection. We investigated the effects of targeted gene therapy on neuronal survival, axonal sprouting of the rubrospinal tract, and motor recovery 12 weeks after unilateral dorsal hemisection at Th8 in rats. In addition to the evaluation of BAG1 and ROCK2 as therapeutic targets in spinal cord injury, we aimed to demonstrate the feasibility and the limits of an AAV-mediated protein over-expression versus AAV.shRNA-mediated down-regulation in this traumatic CNS lesion model. Our results demonstrate that BAG1 and ROCK2-shRNA both promote neuronal survival of red nucleus neurons and enhance axonal sprouting proximal to the lesion.
authors: Department of Neurology, University Medicine Göttingen, Göttingen, Germany.
authors: Malleswari
authors: M
authors: Challagundla
authors: Department of Neurology, University Medicine Göttingen, Göttingen, Germany.
authors: Jan Christoph
authors: JC
authors: Koch
authors: Department of Neurology, University Medicine Göttingen, Göttingen, Germany.
authors: Vinicius Toledo
authors: VT
authors: Ribas
authors: Department of Neurology, University Medicine Göttingen, Göttingen, Germany.
authors: Uwe
authors: U
authors: Michel
authors: Department of Neurology, University Medicine Göttingen, Göttingen, Germany.
authors: Sebastian
authors: S
authors: Kügler
authors: Department of Neurology, University Medicine Göttingen, Göttingen, Germany.
authors: Thomas
authors: T
authors: Ostendorf
authors: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors: Frank
authors: F
authors: Bradke
authors: Department of Neurology, Molecular Neurobiology Laboratory, Heinrich-Heine-University Medical Center Düsseldorf, Düsseldorf, Germany.
authors: Hans Werner
authors: HW
authors: Müller
authors: Department of Neurology, University Medicine Göttingen, Göttingen, Germany.|Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors: Mathias
authors: M
authors: Bähr
authors: Department of Neurology, University Medicine Göttingen, Göttingen, Germany.|Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors: Paul
authors: http://orcid.org/0000-0001-9362-7096
authors: P
authors: Lingor
mesh_terms: D000818:Animals; D001369:Axons; D001483:Base Sequence; D015153:Blotting, Western; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D000229:Dependovirus; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D009416:Nerve Regeneration / Q000502:physiology*; D009474:Neurons / Q000473:pathology*; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D012012:Red Nucleus / Q000473:pathology; D013119:Spinal Cord Injuries / Q000473:pathology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D054460:rho-Associated Kinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C580818:ROCK2 protein, rat; D054460:rho-Associated Kinases
keywords: axonal lesion; gene therapy; red nucleus; regeneration; rho kinase