Laminin and BDNF synergistically induce local translation in axonal growth cones

Didn't your competent? doctor already have SPECIFIC PROTOCOLS ON BDNF AND AXONAL SPROUTING so you can recover properly?

axonal sprouting (52 posts to December 2011)

BDNF (198 posts to April 2011)

laminin (3 posts to October 2014)

Do you prefer your doctor, hospital and board of director's incompetence NOT KNOWING? OR NOT DOING? Your choice; let them be incompetent or demand action!

 Laminin and BDNF synergistically induce local translation in axonal growth cones

Nikita Kirkise1 and Kristy Welshhans1,2* 

1 Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA; 2 Carolina Autism and Neurodevelopment (CAN) Research Center, University of South Carolina, Columbia, SC 29208, USA 

 *Corresponding author: kwelshhans@sc.edu 

 Running title: Laminin regulates local translation

ABSTRACT The laminins are a family of extracellular matrix proteins that regulate numerous cellular processes, including adhesion, neurite outgrowth, and axon guidance. However, it remains unclear whether laminin regulates axon guidance through local translation. Here, we show that laminin is necessary for local translation in axonal growth cones. Local translation is significantly increased in growth cones of embryonic day 17 mouse cortical neurons, either cultured on or acutely stimulated with soluble laminin 111, in the presence of BDNF. When cultured on laminin isoforms 211 or 221 in the presence of BDNF, there was a remarkable decrease in local translation in growth cones. Using a puromycin-proximity ligation assay to examine newly synthesized b-actin specifically, we find a significant increase in growth cones of neurons cultured on laminin 111 in the presence of BDNF. However, soluble laminin 111 alone results in a significant reduction in nascent b-actin protein synthesis. These results indicate that laminin isoforms can act in multiple ways, including synergistically with guidance cues and independently, to modulate local mRNA translation, thereby differentially influencing axon growth and guidance during development. 

 SUMMARY STATEMENT Local translation in axons is critical for axon guidance. Laminin, a key component of the extracellular matrix, is necessary to induce local translation and thus mediate axon growth and guidance. 

 INTRODUCTION Accurate neural wiring is important for the formation of a healthy, functional brain. Changes in neural wiring or the failure to connect with synaptic targets can give rise to various neurological disorders (Van Battum et al., 2015). During development, this neural network is formed through axon guidance, wherein neuronal processes are directed to and establish connections with their synaptic targets (Bellon and Mann, 2018). Axon guidance is mediated by growth cones, which are highly dynamic and motile motor and sensory structures located at the tips of pathfinding axons. Growth cones respond to extracellular cues in their environment, which can be attractive or repulsive, as well as diffusible or contact-mediated (Gomez et al., 1996, Lowery and Vactor, 2009, Bixby and Harris, 1991, McFarlane and Holt, 1997). These cues are sensed by the receptors present on growth cone filopodia and lamellipodia, initiating signaling mechanisms that reorganize the cytoskeleton and allow the growth cone to advance towards, stall, or turn away from the cue (Myers et al., 2011). Contact-mediated cues, such as extracellular matrix (ECM) proteins, are critical in axon guidance. Laminin is a major component of the ECM and is widely expressed in both the peripheral and central nervous systems (Barros et al., 2011, McKerracher et al., 1996, Myers et al., 2011). Numerous studies have reported that laminin regulates axon guidance (Barros et al., 2011, Kuhn et al., 1995, McKerracher et al., 1996, Bonner and O'Connor, 2001, Paulus and Halloran, 2006). Moreover, netrin-1 is an attractive guidance cue for retinal neurons, but when a high concentration of laminin substrate is also present, netrin-1 becomes repellent to these neurons (Hopker et al., 1999). Similarly, retinal ganglion cells collapse in the presence of EphB and laminin, but when L1 is also present, then growth cone pausing occurs (Suh et al., 2004). Thus, laminin acts in concert with other guidance molecules to differentially remodel the cytoskeleton, but we currently have limited knowledge about how this signaling from multiple cues is integrated.

More at link. 

 

Laminin regulates oligodendrocyte development and myelination

 

Do we need this after a stroke? Have we demyelinated neurons in the brain? What does your doctor know about this and what is the protocol to fix it?   

Laminin regulates oligodendrocyte development and myelination

Minkyung Kang, Yao Yao

First published: 12 November 2021

https://doi.org/10.1002/glia.24117

Funding information: National Heart, Lung, and Blood Institute, Grant/Award Number: R01HL146574; National Institute on Aging, Grant/Award Numbers: R21AG064422, R21AG073862, RF1AG065345

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Abstract

Oligodendrocytes are the cells that myelinate axons and provide trophic support to neurons in the CNS. Their dysfunction has been associated with a group of disorders known as demyelinating diseases, such as multiple sclerosis. Oligodendrocytes are derived from oligodendrocyte precursor cells, which differentiate into premyelinating oligodendrocytes and eventually mature oligodendrocytes. The development and function of oligodendrocytes are tightly regulated by a variety of molecules, including laminin, a major protein of the extracellular matrix. Accumulating evidence suggests that laminin actively regulates every aspect of oligodendrocyte biology, including survival, migration, proliferation, differentiation, and myelination. How can laminin exert such diverse functions in oligodendrocytes? It is speculated that the distinct laminin isoforms, laminin receptors, and/or key signaling molecules expressed in oligodendrocytes at different developmental stages are the reasons. Understanding molecular targets and signaling pathways unique to each aspect of oligodendrocyte biology will enable more accurate manipulation of oligodendrocyte development and function, which may have implications in the therapies of demyelinating diseases. Here in this review, we first introduce oligodendrocyte biology, followed by the expression of laminin and laminin receptors in oligodendrocytes and other CNS cells. Next, the functions of laminin in oligodendrocyte biology, including survival, migration, proliferation, differentiation, and myelination, are discussed in detail. Last, key questions and challenges in the field are discussed. By providing a comprehensive review on laminin's roles in OL lineage cells, we hope to stimulate novel hypotheses and encourage new research in the field.

 

Discovery could help scientists stop the "death cascade" of neurons after a stroke

Ask your doctor and hospital what has been done with this information since it came out in Jan 2009. Part of the solution to this problem is quite simple; reduce the size of the tPA bolus substantially because you are using magnetic nanoparticles to deliver it straight to the clot. 

Discovery could help scientists stop the "death cascade" of neurons after a stroke

(PhysOrg.com) -- Distressed swimmers often panic, sapping the strength they need to keep their heads above water until help arrives. When desperate for oxygen, neurons behave in a similar way. They freak out, stupidly discharging energy until they drown in a sea of their own extruded salts. Every year, millions of victims of stroke or brain trauma suffer permanent brain damage because of this mad rush to oblivion that begins once a part of the brain is deprived of blood.

It is well known that a ubiquitous cell receptor drives these oxygen-starved neurons’ lemming-like behavior. But this particular receptor, for the neurotransmitter glutamate, is also responsible for the rapid transmission of information between neurons required for all cognition, among other things. Shutting it off has serious consequences, like coma. Now, a team of scientists at The Rockefeller University has identified a single subunit of this receptor that drives neuronal death. This new discovery suggests that drugs targeting a specific subunit of the complex glutamate receptor might be able to slow brain damage without disrupting other crucial brain functions.

Saving neurons. When normal neurons (top) are subjected to stroke-like damage, they quickly deteriorate and die (center). New research shows that a small portion of the cell’s glutamate receptors, the KA1 subunit, is responsible for this …more

“We have found that you can make mice resistant to this kind of cell death by blocking one piece of the receptor without the terrible side effects you get by blocking the whole thing,” says Sidney Strickland, head of the Laboratory of Neurobiology and Genetics, who directed the research. “Now we can start exploring potential drugs to do that in humans.” The neuronal panic that occurs when a clot or other insult blocks the flow of blood to part of the brain is called excitotoxic neurodegeneration. It results in the brain cells spitting out glutamate, which then accumulates in the synapses between neurons and stimulates the release of more glutamate. It’s a vicious cycle that kills the cells quickly and continues until blood flow is restored. Doctors often treat stroke victims by administering a heavy dose of a clot-buster called tissue plasminogen activator (tPA), a protein that can stimulate the dissolution of clots. Ironically, however, the same drug that does this crucial clot-busting also accelerates the panicky process that kills neurons, research by Strickland and others has shown. Investigating exactly how tPA does that is what led Strickland’s team to the recent discovery.
Neurons are typically couched in laminin, an extracellular matrix protein known to be involved with tPA in the neuronal “death cascade.” The Strickland lab’s experiments, published in The Journal of Cell Biology, show that tPA produces an enzyme that degrades laminin into toxic products that kill the neurons in their midst, specifically by stimulating the production of one of five subunits for a particular kind of glutamate receptor. The overproduction of this specific subunit, KA1, makes the cells hypersensitive to glutamate, which fans the glutamate frenzy leading to their death.

To better understand the process, Zu-Lin Chen and other colleagues at Rockefeller in the Strickland lab and at the University of Leicester in England designed lines of genetically modified mice that lacked either tPA or laminin specifically in the hippocampus, a region of the brain often damaged by stroke. To their surprise, they found that mice without laminin were protected from the typical neural degeneration that follows a simulated stroke in regular mice. They also found that mice with laminin but not tPA were relatively protected.
But when they injected degraded laminin into mouse brains without laminin or tPA they found a similar overproduction of the subunit of the glutamate receptor that they measured when inducing stroke in normal mice. The problem: Laminin, once degraded by tPA, prompts the proliferation of the receptor subunit that makes the cells suicidally sensitive to glutamate. By preventively injecting a molecule that disables that particular subunit, they were able to dramatically reduce the cell death following a stroke. A big plus: The treated mice did not suffer the severe side effects that come with blocking the entire glutamate receptor.
Whether this will turn into a therapy that can be applied after a stroke is uncertain.
“Can you do it after the fact? That will be a question,” Strickland says. “Cell death happens pretty quickly. But it’s an interesting avenue to pursue.”
Reference: The Journal of Cell Biology 183(7): 1299-1313 (December 29, 2008), jcb.rupress.org/cgi/content/abstract/183/7/1299
Provided by Rockefeller University

Polyphenols from green tea prevent antineuritogenic action of Nogo-A via 67-kDa laminin receptor and hydrogen peroxide

I'm sure this is important somehow.

Polyphenols from green tea prevent antineuritogenic action of Nogo-A via 67-kDa laminin receptor and hydrogen peroxide

Usha Gundimeda1, Thomas H. McNeill1, Barsegh A. Barseghian1, William Tzeng1, David Rayudu1, Enrique Cadenas2 and Rayudu Gopalakrishna1,* DOI: 10.1111/jnc.12964

Abstract

Axonal regeneration after injury to the CNS is hampered by myelin-derived inhibitors, such as Nogo-A. Natural products, such as green tea, which are neuroprotective and safe for long-term therapy, would complement ongoing various pharmacological approaches. In this study, using nerve growth factor-differentiated neuronal-like Neuroscreen-1 cells, we show that extremely low concentrations of unfractionated green tea polyphenol mixture (GTPP) and its active ingredient, epigallocatechin-3-gallate (EGCG), prevent both the neurite outgrowth-inhibiting activity and growth cone-collapsing activity of Nogo-66 (C-terminal domain of Nogo-A). Furthermore, a synergistic interaction was observed among GTPP constituents. This preventive effect was dependent on 67-kDa laminin receptor (67LR) to which EGCG binds with high affinity. The antioxidants N-acetylcysteine and cell-permeable catalase abolished this preventive effect of GTPP and EGCG, suggesting the involvement of sublethal levels of H₂O₂ in this process. Accordingly, exogenous sublethal concentrations of H₂O₂, added as a bolus dose (5 μM) or more effectively through a steady-state generation (1-2 μM), mimicked GTPP in counteracting the action of Nogo-66. Exogenous H₂O₂ mediated this action by bypassing the requirement of 67LR.

Taken together, these results show for the first time that GTPP and EGCG, acting through 67LR and elevating intracellular sublethal levels of H₂O₂, inhibit the antineuritogenic action of Nogo-A.