The lipid phosphatase‐like protein PLPPR1 associates with RhoGDI1 to modulate RhoA activation in response to axon growth inhibitory molecules

2021 ◽  
Author(s):  
Chinyere Agbaegbu Iweka ◽  
Rowan K. Hussein ◽  
Panpan Yu ◽  
Yasuhiro Katagiri ◽  
Herbert M. Geller
Keyword(s):  
Axon Growth ◽  
Rhoa Activation ◽  
Lipid Phosphatase ◽  
Growth Inhibitory ◽  
Inhibitory Molecules

scholarly journals Poly(ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration

2015 ◽  
Vol 112 (49) ◽  
pp. 15220-15225 ◽  
Author(s):  
Camille Brochier ◽  
James I. Jones ◽  
Dianna E. Willis ◽  
Brett Langley
Keyword(s):  
Molecular Mechanisms ◽  
Axon Regeneration ◽  
Neuronal Loss ◽  
Axon Growth ◽  
Axonal Growth ◽  
Growth Inhibitory ◽  
Physical Barriers ◽  
The Central Nervous System ◽  
Novel Target ◽  
Inhibitory Molecules

Therapeutic options for the restoration of neurological functions after acute axonal injury are severely limited. In addition to limiting neuronal loss, effective treatments face the challenge of restoring axonal growth within an injury environment where inhibitory molecules from damaged myelin and activated astrocytes act as molecular and physical barriers. Overcoming these barriers to permit axon growth is critical for the development of any repair strategy in the central nervous system. Here, we identify poly(ADP-ribose) polymerase 1 (PARP1) as a previously unidentified and critical mediator of multiple growth-inhibitory signals. We show that exposure of neurons to growth-limiting molecules—such as myelin-derived Nogo and myelin-associated glycoprotein—or reactive astrocyte-produced chondroitin sulfate proteoglycans activates PARP1, resulting in the accumulation of poly(ADP-ribose) in the cell body and axon and limited axonal growth. Accordingly, we find that pharmacological inhibition or genetic loss of PARP1 markedly facilitates axon regeneration over nonpermissive substrates. Together, our findings provide critical insights into the molecular mechanisms of axon growth inhibition and identify PARP1 as an effective target to promote axon regeneration.

scholarly journals Non-viral Vector Mediated RNA Interference Technology for Central Nervous System Injury

2016 ◽  
Vol 3 (1) ◽  
Author(s):  
Christian Macks ◽  
Jeoung Soo Lee
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rna Interference ◽  
Axonal Regeneration ◽  
Viral Vector ◽  
Traumatic Injury ◽  
Neurite Growth ◽  
Cns Injury ◽  
Growth Inhibitory ◽  
Inhibitory Molecules

AbstractNeuronal axons damaged by traumatic injury are unable to spontaneously regenerate in the mammalian adult central nervous system (CNS), causing permanent motor, sensory, and cognitive deficits. Regenerative failure in the adult CNS results from a complex pathology presenting multiple barriers, both the presence of growth inhibitors in the extrinsic microenvironment and intrinsic deficiencies in neuronal biochemistry, to axonal regeneration and functional recovery. There are many strategies for axonal regeneration after CNS injury including antagonism of growth-inhibitory molecules and their receptors, manipulation of cyclic nucleotide levels, and delivery of growth-promoting stimuli through cell transplantation and neurotrophic factor delivery. While all of these approaches have achieved varying degrees of improvement in plasticity, regeneration, and function, there is no clinically effective therapy for CNS injury. RNA interference technology offers strategies for improving regeneration by overcoming the aspects of the injured CNS environment that inhibit neurite growth. This occurs through the knockdown of growth-inhibitory molecules and their receptors. In this review, we discuss the current state of RNAi strategies for the treatment of CNS injury based on non-viral vector mediated delivery.

scholarly journals Retinal Ganglion Cell Survival and Axon Regeneration after Optic Nerve Transection is Driven by Cellular Intravitreal Sciatic Nerve Grafts

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1335
Author(s):  
Zubair Ahmed ◽  
Ellen L. Suggate ◽  
Ann Logan ◽  
Martin Berry
Keyword(s):  
Nervous System ◽  
Optic Nerve ◽  
Sciatic Nerve ◽  
Schwann Cells ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Retinal Ganglion ◽  
Nerve Transection ◽  
Nerve Grafts ◽  
Growth Inhibitory

Neurotrophic factors (NTF) secreted by Schwann cells in a sciatic nerve (SN) graft promote retinal ganglion cell (RGC) axon regeneration after either transplantation into the vitreous body of the eye or anastomosis to the distal stump of a transected optic nerve. In this study, we investigated the neuroprotective and growth stimulatory properties of SN grafts in which Schwann cells had been killed (acellular SN grafts, ASN) or remained intact (cellular SN grafts, CSN). We report that both intravitreal (ivit) implanted and optic nerve anastomosed CSN promote RGC survival and when simultaneously placed in both sites, they exert additive RGC neuroprotection. CSN and ASN were rich in myelin-associated glycoprotein (MAG) and axon growth-inhibitory ligand common to both the central nervous system (CNS) and peripheral nervous system (PNS) myelin. The penetration of the few RGC axons regenerating into an ASN at an optic nerve transection (ONT) site is limited into the proximal perilesion area, but is increased >2-fold after ivit CSN implantation and increased 5-fold into a CSN optic nerve graft after ivit CSN implantation, potentiated by growth disinhibition through the regulated intramembranous proteolysis (RIP) of p75NTR (the signalling trans-membrane moiety of the nogo-66 trimeric receptor that binds MAG and associated suppression of RhoGTP). Mϋller cells/astrocytes become reactive after all treatments and maximally after simultaneous ivit and optic nerve CSN/ASN grafting. We conclude that simultaneous ivit CSN plus optic nerve CSN support promotes significant RGC survival and axon regeneration into CSN optic nerve grafts, despite being rich in axon growth inhibitory molecules. RGC axon regeneration is probably facilitated through RIP of p75NTR, which blinds axons to myelin-derived axon growth-inhibitory ligands present in optic nerve grafts.

scholarly journals Plasticity-related Gene 5 (PRG5) Induces Filopodia and Neurite Growth and Impedes Lysophosphatidic Acid– and Nogo-A–mediated Axonal Retraction

2010 ◽  
Vol 21 (4) ◽  
pp. 521-537 ◽  
Author(s):  
Thomas Broggini ◽  
Robert Nitsch ◽  
Nic E. Savaskan
Keyword(s):  
Brain Lesion ◽  
Rho Kinase ◽  
Axon Growth ◽  
Neurite Growth ◽  
Related Gene ◽  
Independent Manner ◽  
Spinal Cord Development ◽  
Axon Elongation ◽  
Growth Inhibitory ◽  
Kinase Pathway

Members of the plasticity-related gene (PRG1-4) family are brain-specific integral membrane proteins and implicated in neuronal plasticity, such as filopodia formation and axon growth after brain lesion. Here we report on the cloning of a novel member of the PRG family, PRG5, with high homologies to PRG3. PRG5 is regulated during brain and spinal cord development and is exclusively allocated within the nervous system. When introduced in neurons, PRG5 is distributed in the plasma membrane and induces filopodia as well as axon elongation and growth. Conversely, siRNA mediated knockdown of PRG5 impedes axon growth and disturbs filopodia formation. Here we show that PRG5 induces filopodia growth independently of Cdc42. Moreover, axon collapse and RhoA activation induced by LPA and myelin-associated neurite inhibitor Nogo-A is attenuated in the presence of PRG5, although direct activation of the RhoA-Rho-PIP5K kinase pathway abolishes PRG5 -formed neurites. Thus, we describe here the identification of a novel member of the PRG family that induces filopodia and axon elongation in a Cdc42-independent manner. In addition, PRG5 impedes brain injury-associated growth inhibitory signals upstream of the RhoA-Rho kinase pathway.

Chondroitin 6-sulphate synthesis is up-regulated in injured CNS, induced by injury-related cytokines and enhanced in axon-growth inhibitory glia

2005 ◽  
Vol 21 (2) ◽  
pp. 378-390 ◽  
Author(s):  
Francesca Properzi ◽  
Daniela Carulli ◽  
Richard A. Asher ◽  
Elizabeth Muir ◽  
Luiz M. Camargo ◽  
...  
Keyword(s):  
Axon Growth ◽  
Growth Inhibitory

scholarly journals Rapid and strain-specific resistance evolution of Staphylococcus aureus against inhibitory molecules secreted by Pseudomonas aeruginosa

2021 ◽  
Author(s):  
Selina Niggli ◽  
Lucy Poveda ◽  
Jonas Grossmann ◽  
Rolf Kuemmerli
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Treatment Options ◽  
Membrane Transporters ◽  
Resistance Evolution ◽  
Virulence Traits ◽  
Growth Inhibitory ◽  
Inhibitory Molecules ◽  
And Staphylococcus Aureus ◽  
Polymicrobial Infections

Pseudomonas aeruginosa and Staphylococcus aureus frequently occur together in polymicrobial infections, and there is evidence that their interactions negatively affect disease outcome in patients. At the molecular level, interactions between the two bacterial taxa are well-described, with P. aeruginosa usually being the dominant species suppressing S. aureus through a variety of inhibitory molecules. However, in polymicrobial infections, the two species interact over prolonged periods of time, and S. aureus might evolve resistance against inhibitory molecules deployed by P. aeruginosa. Here, we used experimental evolution to test this hypothesis by exposing three different S. aureus strains (Cowan I, 6850, JE2) to the growth-inhibitory supernatant of P. aeruginosa PAO1 over 30 days. We found that all three S. aureus strains rapidly evolved resistance against inhibitory molecules and show that (i) adaptations were strain-specific; (ii) resistance evolution affected the expression of virulence traits; and (iii) mutations in membrane transporters were the most frequent evolutionary targets. Our work indicates that adaptations of S. aureus to co-infecting pathogens could increase virulence and decrease antibiotic susceptibility, because both virulence traits and membrane transporters involved in drug resistance were under selection. Thus, pathogen co-evolution could exacerbate infections and compromise treatment options.

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