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      Tyrosine-mutated AAV2-mediated shRNA silencing of PTEN promotes axon regeneration of adult optic nerve

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      Author(s): 1 , 2 , 1 , 1 , 1 , *
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      Journal: PLoS ONE
      Publisher: Public Library of Science

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          Abstract

          Activating PI3K/AKT/mTOR signaling pathway via deleting phosphatase and tensin homolog (PTEN) has been confirmed to enhance intrinsic growth capacity of neurons to facilitate the axons regeneration of central nervous system after injury. Considering conditional gene deletion is currently not available in clinical practice, we exploited capsid residue tyrosine 444 to phenylalanine mutated single-stranded adeno-associated virus serotype 2 (AAV2) as a vector delivering short hairpin RNA to silence PTEN to promote retinal ganglion cells (RGCs) survival and axons regeneration in adult rat optic nerve axotomy paradigm. We found that mutant AAV2 displayed higher infection efficiency to RGCs and Müller cells by intravitreal injection, mediated PTEN suppression, resulted in much more RGCs survival and more robust axons regeneration compared with wild type AAV2, due to the different extent of the mTOR complex-1 activation and glutamate aspartate transporter (GLAST) regulation. These results suggest that high efficiency AAV2-mediated PTEN knockdown represents a practicable therapeutic strategy for optic neuropathy.

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          Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway.

          Kevin Kyungsuk Park, Kai Liu, Yang Hu … (2008)
          The failure of axons to regenerate is a major obstacle for functional recovery after central nervous system (CNS) injury. Removing extracellular inhibitory molecules results in limited axon regeneration in vivo. To test for the role of intrinsic impediments to axon regrowth, we analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. Deletion of PTEN (phosphatase and tensin homolog), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, in adult retinal ganglion cells (RGCs) promotes robust axon regeneration after optic nerve injury. In wild-type adult mice, the mTOR activity was suppressed and new protein synthesis was impaired in axotomized RGCs, which may contribute to the regeneration failure. Reactivating this pathway by conditional knockout of tuberous sclerosis complex 1, another negative regulator of the mTOR pathway, also leads to axon regeneration. Thus, our results suggest the manipulation of intrinsic growth control pathways as a therapeutic approach to promote axon regeneration after CNS injury.
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            PTEN Deletion Enhances the Regenerative Ability of Adult Corticospinal Neurons

            Kai Liu, Qiao-Yi Lu, Jae K. Lee … (2010)
            Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. Here we demonstrate a critical involvement of PTEN/mTOR in controlling the regenerative capacity of mouse corticospinal neurons. Upon the completion of development, the regrowth potential of CST axons lost and this is accompanied by a down-regulation of mTOR activity in corticospinal neurons. Axonal injury further diminishes neuronal mTOR activity in these neurons. Forced up-regulation of mTOR activity in corticospinal neurons by conditional deletion of PTEN, a negative regulator of mTOR, enhances compensatory sprouting of uninjured CST axons and even more strikingly, enables successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possess the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.
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              Sustained axon regeneration induced by co-deletion of PTEN and SOCS3

              Fang Sun, Kevin Park, Stephane Belin … (2011)
              A formidable challenge in neural repair in the adult central nervous system (CNS) is the long distances that regenerating axons often need to travel in order to reconnect with their targets. Thus, a sustained capacity for axon regeneration is critical for achieving functional restoration. Although deletion of either Phosphatase and tensin homolog (PTEN), a negative regulator of mammalian target of rapamycin (mTOR), or suppressor of cytokine signaling 3 (SOCS3), a negative regulator of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, in adult retinal ganglion cells (RGCs) individually promoted significant optic nerve regeneration, such regrowth tapered off around two weeks after the crush injury 1,2 . Remarkably, we now find that simultaneous deletion of both PTEN and SOCS3 enables robust and sustained axon regeneration. We further show that PTEN and SOCS3 regulate two independent pathways that act synergistically to promote enhanced axon regeneration. Gene expression analyses suggest that double deletion not only results in the induction of many growth-related genes, but also allows RGCs to maintain the expression of a repertoire of genes at the physiological level after injury. Our results reveal concurrent activation of mTOR and STAT3 pathways as a key for sustaining long-distance axon regeneration in adult CNS, a crucial step toward functional recovery.
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                Author and article information

                Contributors
                Steven Barnes: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 21 March 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 3
                Electronic Location Identifier: e0174096
                Affiliations
                [1 ]Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
                [2 ]Department of Ophthalmology, the Second People´s Hospital of Changshu, Changshu, Jiangsu Province, China
                Dalhousie University, CANADA
                Author notes

                Competing Interests: The authors declare no competing financial interests.

                • Conceptualization: ZRH QHL.

                • Data curation: ZRH QHL.

                • Formal analysis: ZRH ZZH PX QHL.

                • Funding acquisition: ZRH.

                • Investigation: ZRH ZZH PX.

                • Methodology: ZRH QHL.

                • Project administration: PX QHL.

                • Resources: QHL.

                • Supervision: QHL.

                • Validation: QHL.

                • Writing – original draft: ZRH ZZH QHL.

                • Writing – review & editing: QHL.

                Article
                Publisher ID: PONE-D-16-43752
                DOI: 10.1371/journal.pone.0174096
                PMC ID: 5360277
                PubMed ID: 28323869
                SO-VID: 7428e216-3f1b-4f2e-bb23-eeaec3f0c927
                Copyright © © 2017 Huang et al
                License:

                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
                Date received : 3 November 2016
                Date accepted : 4 March 2017
                Page count
                Figures: 11, Tables: 0, Pages: 19
                Funding
                Funded by: Research Foundation of Jiangsu Provincial Commission of Health and Family Planning
                Award ID: No.201653
                Award Recipient :
                This work was supported by the Research Foundation of Jiangsu Provincial Commission of Health and Family Planning (NO.H201653, http://www.jswst.gov.cn/jsswshjhsywyh/). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Neurons
                Subject: Afferent Neurons
                Subject: Retinal Ganglion Cells
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Cellular Neuroscience
                Subject: Neurons
                Subject: Afferent Neurons
                Subject: Retinal Ganglion Cells
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Neurons
                Subject: Ganglion Cells
                Subject: Retinal Ganglion Cells
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Cellular Neuroscience
                Subject: Neurons
                Subject: Ganglion Cells
                Subject: Retinal Ganglion Cells
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Ocular Anatomy
                Subject: Retina
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Ocular Anatomy
                Subject: Retina
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Neurons
                Subject: Nerve Fibers
                Subject: Axons
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Cellular Neuroscience
                Subject: Neurons
                Subject: Nerve Fibers
                Subject: Axons
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Morphogenesis
                Subject: Regeneration
                Subject: Nerve Regeneration
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Organism Development
                Subject: Regeneration
                Subject: Nerve Regeneration
                Subject: Medicine and Health Sciences
                Subject: Surgical and Invasive Medical Procedures
                Subject: Nervous System Procedures
                Subject: Axotomy
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Optic Nerve
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Optic Nerve
                Subject: Research and Analysis Methods
                Subject: Imaging Techniques
                Subject: Fluorescence Imaging
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Eyes
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Eyes
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Eyes
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Ocular System
                Subject: Eyes
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files.

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