Inhibition of miR-383 promotes axon regeneration following injury

Authors:
C. JUZWIK, B. MORQUETTE, Y. ZHANG, E. GOWING, C. BOUDREAU-PINSONNEAULT, V. VANGOOR, R. PASTERKAMP, C. MOORE, A. BAR-OR, A. E. FOURNIER

Camille Juzwik PhD candidate at Fournier Lab McGill University

Lab Abstract:

Neuroinflammation can positively influence axon regeneration following injury in the central nervous system (CNS) but the molecular mechanisms underlying this effect are not fully understood. We have evaluated how microRNAs may be regulated in the context of inflammation because they target multiple mRNAs simultaneously and may help to identify signalling hubs that can be targeted to promote regeneration. We identified miR-383 as a miRNA that is down regulated in neurons in response to neurite outgrowth-promoting astrocyte conditioned media (ACM). We also found that miR-383 was down regulated in Retinal Ganglion Cells (RGCs) exposed to zymosan, a yeast cell wall protein that stimulates inflammation in the eye and promotes axon regeneration following optic nerve crush. miR383 down regulation promotes axon growth in vitro and injection of a miR-383 inhibitor into the eye promotes axon regeneration following optic nerve crush. Previous studies have demonstrated that astrocyte-derived CNTF, signals to injured RGCs and promotes their regeneration in response to zymosan injection. We found that neurons treated with CNTF down regulated the expression of miR-383. Further, we have acquired evidence that inhibiting miR-383 de-represses the expression of mitochondrial antioxidant genes and microtubule-associated proteins that are important for the pro-regenerative effects of the miR383 inhibitor. Together, we have implicated miR-383 as a molecule that suppresses axon regeneration and that can be further explored to identify novel signalling hubs that may be targeted to promote repair.

*C. JUZWIK1, B. MORQUETTE1, Y. ZHANG1, E. GOWING2, C. BOUDREAU-PINSONNEAULT3, V. VANGOOR4, R. PASTERKAMP4, C. MOORE5, A. BAR-OR6, A. E. FOURNIER1;
1Dept Neurol & Neurosur, McGill Univ., Montreal, QC, Canada; 2CRCHUM, Montreal, QC, Canada; 3Inst. De Recherche Clinique De Montréal, Montreal, QC, Canada; 4UMC Utrecht, Utrecht, Netherlands; 5Mem. Univ., St John’s, NL, Canada; 6Perelman Sch. of Med., Philadelphia, PA. Inhibition of miR-383 promotes axon regeneration following injury. Program No. 115.11. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

Grant Support: MSSOC Grant

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, spinal cord injury research, Stem Cell Research | Tagged , ,

Merry Christmas

Happy Holidays from Spinal Cord Injury Research and Science Report – – thank you to our followers in 175 countries around the world.

 

 

 

Posted in Uncategorized

Epidural Spinal Cord Stimulation Acutely Modulates Lower Urinary Tract and Bowel Function Following Spinal Cord Injury: A Case Report

Authors: Matthias Walter, Amanda H. X. Lee, Alex Kavanagh, Aaron A. Phillips and Andrei V. Krassioukov

“Regaining control of autonomic functions such as those of the cardiovascular system, lower urinary tract and bowel, rank among the most important health priorities for individuals living with spinal cord injury (SCI). Recently our research provided evidence that epidural spinal cord stimulation (ESCS) could acutely modulate autonomic circuits responsible for cardiovascular function after SCI. This finding raised the question of whether ESCS can be used to modulate autonomic circuits involved in lower urinary tract and bowel control after SCI. We present the case of a 32-year-old man with a chronic motor-complete SCI (American Spinal injury Association Impairment Scale B) at the 5th cervical spinal segment.”

LINK: Read the Full Publication at Frontiers in Physiology

Posted in Chronic Spinal Cord Injury Research, Rehabilitation, spinal cord injury research | Tagged , , , ,

SCI Research starts a big New Year

SCI 2020

In preparation for the February NIH SCI 2020,  this is the LINK you will be using to watch the meeting live on the day of the event.   https://videocast.nih.gov/
Tuesday February 12th at 8:AM Eastern Time
Wednesday February 13th at 8:00 AM Eastern Time

To express your opinion and voice for the consumer panel, the North American Spinal Cord Injury Research Consortium (NASCIC) is looking to gather information from the community on issues in SCI research that are important from the consumer perspective.

https://www.surveymonkey.com/r/SCI2020

SCI 2020: Planning for a Decade for Disruption in Spinal Cord Injury Research will bring together experts in the field of spinal cord injury research to debate the state of science and opportunities for moving forward in the next decade, in a panel and audience participation focused format.

The objectives are:

1) To provide a critical multidisciplinary assessment of recent progress and gaps in SCI research across the basic, translational and clinical spectrum,

2) To identify the key questions and top priorities to move the SCI field forward in the coming decade

3) To disrupt existing silos and create multidisciplinary collaborations that will address the defined priorities for the short and long term.

Author: NINDS NIH       Runtime: 10 hours

 

Posted in Chronic Spinal Cord Injury Research, spinal cord injury research

Dustin Shillcox explains epidural stimulation that restores movement after SCI

“In 2013, Dustin Shillcox became 1 of the first 4 people in the world to be a part of groundbreaking epidural stimulation research at the University of Louisville.  A set of electrodes was surgically implanted onto his spinal cord below the level of his injury and a small power pack was implanted into his abdomen.  When the pack is turned on, an electric current is sent to the electrodes, which stimulates his spinal cord into action.”

See the full article at NeuroHope by Chris Leeuw along with the the latest video!

Posted in Chronic Spinal Cord Injury Research, Rehabilitation, spinal cord injury research | Tagged , , | 1 Comment

First Year Update at Brooks Cybernic Treatment Center Utilizing “HAL” for SCI

The Brooks Cybernic Treatment Center is the only US-based facility offering HAL technology to those with a spinal cord injury. Cybernics is a new academic field that is centered on cybernetics, mechatronics and informatics fused with various other fields including brain/neuroscience, robotics, biology, behavioral science, psychology, law, ethics, and business administration. In short, Cybernics is the integration of human, robotics and information systems.

It’s been a busy year in the Brooks Cybernic Treatment Center and we have a lot to come in 2019!

For more info about the Brooks Cybernic Treatment Center: https://brooksrehab.org/cyberdyne/

Visit us! https://www.brooksrehab.org

Brooks Rehabilitation Spinal Cord Injury Studies Enrollment LINK

Behind the Scenes

Posted in Chronic Spinal Cord Injury Research, Rehabilitation | Tagged ,

Continued development of human neural stem cell grafts into non-human primate spinal cord contusion or hemisection lesions

Authors:
*E. S. ROSENZWEIG, J. H. BROCK, P. LU, H. KUMAMARU, J. L. WEBER, C. A. WEINHOLTZ, R. MOSEANKO, S. HAWBECKER, R. PENDER, C. L. CRUZEN, E. A. SALEGIO,, J. HUIE, C. ALMEIDA, Y. S. NOUT-LOMAS, L. A. HAVTON, A. R. FERGUSON, M. S. BEATTIE, J. C. BRESNAHAN, M. H. TUSZYNSKI

Ephron Rosenzweig, PhD Assistant Adjunct Professor, UCSD Neuroscience – University of California San Diego

Lab Abstract:
We previously demonstrated that human neural stem cells (hNSCs) and multipotent neural progenitor cells (hNPCs) grafted into sites of rodent spinal cord injury (SCI) survive, extend axons, form synapses, support host axon regeneration, and improve functional recovery (Lu et al., Cell 2012; Lu et al., Neuron 2014; Kadoya et al., Nat Med 2016). Recently, we published the first steps in translation of this approach to non-human primates using hNSCs derived from fetal tissue (Rosenzweig et al., Nat Med 2018).
We now discuss continued development of this approach, specifically addressing issues that will enable potential translation to human clinical trials. We have developed a human embryonic stem cell-derived neural stem cell line driven to a spinal cord identity (H9-scNSC; Kumamaru et al., Nat Methods 2018) as a candidate optimal cell type for human translation. In the present work, we have grafted this lead candidate translational cell line to rhesus monkeys that have undergone either C7 unilateral spinal cord hemisection (Rosenzweig et al., Nat Neurosci 2010) or C7 unilateral spinal cord contusion (Salegio et al., J Neurotrauma 2016). We find that:
1) H9-scNSC grafts placed into sites of C7 hemisection SCI survive, extend axons, form synapses, and support host axon regeneration. Analysis of possible graft-associated functional improvement is ongoing.
2) H9-scNSC grafts placed into sites of C7 unilateral contusion
SCI survive, extend axons, form synapses, and support host axon regeneration. Analysis of possible graft-associated functional improvement is ongoing.
3) In the first subject maintained for 1.5 years after grafting, the graft survived, extended axons, and supported host axon regeneration. Critically, there was no sign of excessive graft growth or other safety problems.

Abstract Citation
*E. S. ROSENZWEIG1, J. H. BROCK1,2, P. LU1,2, H. KUMAMARU1, J. L. WEBER1, C. A. WEINHOLTZ1, R. MOSEANKO3, S. HAWBECKER3, R. PENDER3, C. L. CRUZEN3, E. A. SALEGIO3, J. HUIE4, C. ALMEIDA4, Y. S. NOUT-LOMAS5, L. A. HAVTON6, A. R. FERGUSON4,7, M. S. BEATTIE4, J. C. BRESNAHAN4, M. H. TUSZYNSKI1,2;
1Neurosciences, Univ. of California San Diego Dept. of Neurosciences, La Jolla, CA; 2VA Med. Ctr. San Diego, San Diego, CA; 3California Natl. Primate Res. Center, Univ. Calif. Davis, Davis, CA; 4Dept. of Neurolog. Surgery, Brain and Spinal Injury Ctr. (BASIC), UCSF, San Francisco, CA; 5Col. of Vet. Med. and Biomed. Sciences, Colo. State Univ., Fort Collins, CO; 6Dept. of Neurol., UCLA, Los Angeles, CA; 7VA Med. Ctr. San Francisco, San Francisco, CA. Continued development of human neural stem cell grafts into non-human primate spinal cord contusion or hemisection lesions. Program No. 138.11. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

Grant Support
VA IP50RX001045 RR&D B7332R
Grant Support
NIH R01-NS042291
NIH NCRR P51 OD011107-56
Craig H Neilsen Foundation
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
Bernard and Anne Spitzer Charitable Trust
Grant Support
DOD CDMRP SC170233
Grant Support
NIH R01-NS104442

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, spinal cord injury research, Stem Cell Research | Tagged ,

Overexpression of protrudin in primary cortical neurons enhances regeneration after laser axotomy through multiple mechanisms

Authors:
V. PETROVA, R.EVA, J.W. FAWCETT

Veselina Petrova, PhD student in James Fawcett lab.


Lab Abstract:

Numerous extracellular and intracellular processes contribute to the failure of long-range regeneration in the adult central nervous system (CNS) after injury. One reason why adult CNS axons have poor regenerative capabilities is that a developmental change occurs where essential growth molecules such as integrins and growth factor receptors become excluded from axons. These growth-promoting molecules are normally transported along axons in Rab11-positive recycling endosomes by motor proteins/adaptor complexes. However, this transport declines with maturation leading to a decline in regenerative capacity. Protrudin, a member of the ZFYVE family of zinc-binding proteins is a membrane-associated protein involved in neurite outgrowth and directional membrane trafficking in HeLa, PC12 and primary hippocampal cells (Shirane et al., 2006). Phosphorylated protrudin preferentially binds to Rab11-GDP, an association which is required for neurite outgrowth and for anterograde movement of this complex.
We hypothesised that increasing the phospho-protrudin/Rab11 interaction would result in anterograde transport of growth-promoting molecules to the tip of injured axons enabling regeneration of primary cortical neurons after laser axotomy. To test this, two phosphomimetic forms of protrudin were created at phosphorylation sites known to play an important role for its association with Rab11. We found that both constitutively phosphorylated protrudin forms (64%, 70%) and also wild-type protrudin (60%) increased the proportion of regenerating axons compared to control (27%). Live-cell imaging experiments are currently being performed to investigate whether the increase in regenerative capacity is indeed due to its association with Rab11 and increased anterograde transport of integrins. Protrudin is a complex molecule with numerous cellular functions such as ER shaping, vesicular transport, interactions with spastin – a microtubule-severing protein and many more. In order to unpick the mechanisms of action of protrudin on regeneration, five mutants were created – each targeting a specific region of the protein important for its involvement in various molecular pathways (ΔFYVE, ΔRab11-binding-domain, ΔKIF5, ΔFFAT, ΔSpastin). These mutants were overexpressed in primary cortical neurons and their effects on regeneration were tested. Protrudin was found to promote regeneration through multiple mechanisms, some of which, such as ER function have not previously been associated with the process of axon regeneration. Protrudin’s ability to promote regeneration is currently being tested in vivo in models of acute and chronic injury.

*V. PETROVA1, R. EVA1, J. W. FAWCETT1,2;
1Cambridge Univ., Cambridge, United Kingdom; 2Inst. of Exptl. Med., Ctr. of Reconstructive Neurosci., Prague, Czech Republic. Overexpression of protrudin in primary cortical neurons enhances regeneration after laser axotomy through multiple mechanisms. Program No. 115.05. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

Grant Support: MRC Grant R004463, MRC Grant G1000864, Gates Cambridge Studentship, Gates Cambridge Academic Development Award,
International Foundation for Research in Paraplegia P172

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, spinal cord injury research, Stem Cell Research | Tagged ,

Lin28 protein regulates CNS axon regeneration in adult mammalians

Authors: Shuxin LI, F.NATHAN, Y.OHTAKE, H.GUO, A.SAMI

Shuxin Li, MD, PhD.
Associate Professor, Anatomy and Cell Biology
Associate Professor, Shriners Hospitals Pediatric Research Center

Lab Abstract:
Severed CNS axons fail to regenerate in adult mammals and there are no effective regenerative strategies to treat patients with CNS injuries. Several genes, including PTEN and Krüppel-like factors, regulate intrinsic growth capacity of mature neurons. However, none of these approaches were translated to clinics yet and thus there is a persistent need to identify better targets and improved delivery methods. Lin28, an RNA-binding protein, enhances translation of multiple genes including metabolic enzymes for increasing glycolysis and oxidative phosphorylation, and is essential for cell development and pluripotency in worms and mammals. Lin28 is a gatekeeper molecule to control switch between pluripotency and committed cells and its reactivation stimulates repair of several tissue systems, including hair, cartilage, bone, and mesenchyme. In this study, we reprogram mature CNS neurons with Lin28 activation to increase their growth capacity after CNS injuries. Especially, we evaluated the role of Lin28a in regulating regenerative capacity of different types of CNS neurons in adult mammals. Using neuron-specific Thy1 promoter, we generated transgenic mice that overexpress Lin28a protein in multiple neuronal populations, including multiple descending projection tracts and retinal ganglion cells. We demonstrate that upregulation of Lin28a in adult transgenic mice induces significant long distance regeneration of descending motor axons after spinal cord injury and optic fibres following optic nerve axotomy. Importantly, overexpression of Lin28a by post-injury treatment with AAV2 vector also stimulates dramatic regeneration of corticospinal tracts after spinal cord injury and optic axons after optic injury. Upregulation of Lin28a also enhances survival of retinal ganglion cells after injury and activity of Akt/mTOR signalling pathway in various CNS neurons. Therefore, Lin28a is critical for regulating growth capacity of CNS neurons and may become an important molecular target for treating for CNS injuries, including traumatic spinal cord and brain injury.

*S. LI, F. NATHAN, Y. OHTAKE, H. GUO, A. SAMI;
Shriners Hosp. Pediatric Res. Ctr., Temple Univ. Sch. of Med., Philadelphia, PA. Lin28 protein regulates CNS axon regeneration in adult mammalians. Program No. 115.07. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

Grant Support: NIH 1R01NS079432 and 1R01EY024575,  SHC-85100, SHC-86300-PHI, SHC-86200-PHI-16, SHC-85112-PHI-18


Also taking place in the Li Lab: 

Lab 2018 NIH Grant:  Acute Neural Injury and Epilepsy Study Section (ANIE) {R01-NS105961-01}  Develop a combinatorial therapy for spinal cord injury 

Temple Health Article:  Temple Scientists Identify Novel Target for Neuron Regeneration and Functional Recovery in Spinal Cord Injury

Technology Networks:  Protein Therapy Boosts Spinal Cord Regeneration in Mice

Molecular Therapy: Promoting axon regeneration in adult CNS by targeting liver kinase B1

 

Posted in Chronic Spinal Cord Injury Research, Neuroscience Abstracts, Regenerative Medicine, spinal cord injury research, Stem Cell Research | Tagged , , , | 1 Comment

Case Western Reserve Researchers Restore Breathing and Partial Forelimb Function in Rats with Chronic Spinal Cord Injuries

Promising results provide hope for humans suffering from chronic paralysis

“Millions of people worldwide are living with chronic spinal cord injuries, with 250,000 to 500,000 new cases each year—most from vehicle crashes or falls. The most severe spinal cord injuries completely paralyze their victims and more than half impair a person’s ability to breathe. Now, a breakthrough study published in Nature Communications has demonstrated, in animal models of chronic injury, that long-term, devastating effects of spinal cord trauma on breathing and limb function may be reversible.

The new study describes a treatment regimen that helps reawaken certain special types of nerve cells that can regenerate extensions, called axons, within the damaged spinal cord. Rats with spinal cords half severed at the second cervical vertebrae (C2) regained complete diaphragm and partial forelimb function on the severed side after treatment. The recuperative effects of the therapy were fully maintained six months after treatment end.”

SEE THE FULL ARTICLE AT CASE WESTERN RESERVE NEWS CENTER:

Posted in Chronic Spinal Cord Injury Research, Regenerative Medicine, spinal cord injury research | Tagged , ,