Neuronal Signaling Involved in Neuronal Polarization and Growth: Lipid Rafts and Phosphorylation

Igarashi, Michihiro; Honda, Atsuko; Kawasaki, Asami; Nozumi, Motohiro

doi:10.3389/fnmol.2020.00150

Cited by 22 publications

(14 citation statements)

References 160 publications

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“…There is little knowledge about the differential distribution and composition of lipid rafts in different types of neurons, axonal and dendritic compartments and the changes during maturation of the CNS. Neurons are highly polarized cells, and signaling molecules that play a role in the specification of the somatodendritic and axonal compartments also reside in lipid rafts [ 162 ]. Lipid rafts are highly abundant in dendrites of cultured hippocampal neurons, and a variety of postsynaptic proteins are associated with them [ 163 ].…”

Section: Discussionmentioning

confidence: 99%

One Raft to Guide Them All, and in Axon Regeneration Inhibit Them

Hernaiz-Llorens

Martínez-Mármol

Roselló-Busquets

et al. 2021

IJMS

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Central nervous system damage caused by traumatic injuries, iatrogenicity due to surgical interventions, stroke and neurodegenerative diseases is one of the most prevalent reasons for physical disability worldwide. During development, axons must elongate from the neuronal cell body to contact their precise target cell and establish functional connections. However, the capacity of the adult nervous system to restore its functionality after injury is limited. Given the inefficacy of the nervous system to heal and regenerate after damage, new therapies are under investigation to enhance axonal regeneration. Axon guidance cues and receptors, as well as the molecular machinery activated after nervous system damage, are organized into lipid raft microdomains, a term typically used to describe nanoscale membrane domains enriched in cholesterol and glycosphingolipids that act as signaling platforms for certain transmembrane proteins. Here, we systematically review the most recent findings that link the stability of lipid rafts and their composition with the capacity of axons to regenerate and rebuild functional neural circuits after damage.

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Section: Discussionmentioning

confidence: 99%

One Raft to Guide Them All, and in Axon Regeneration Inhibit Them

Hernaiz-Llorens

Martínez-Mármol

Roselló-Busquets

et al. 2021

IJMS

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“…Found in plasma membranes, intracellular membranes, and extracellular vesicles, lipid rafts are dynamic, nanoscopic (10–200 nm), transient, mobile, liquid-ordered (Lo) domains formed as a result of thermodynamically driven LLPS [ 189 , 190 , 191 , 192 , 193 ]. Compared to non-raft domains, the lower-fluidity transient lipid rafts serve as signaling hotspots that respond to external stimuli by modulating their composition and size, and increasing or lowering the concentration of signal transduction proteins [ 93 , 194 , 195 ]. When formed under pathological inflammatory conditions, lipid rafts become enlarged inflammarafts (i-rafts), signaling platforms that contain activated receptors and adaptor molecules associated with inflammatory cellular processes in diseased states [ 196 , 197 , 198 ].…”

Section: The Interdependence Between Membranes and Membraneless Organellesmentioning

confidence: 99%

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

Loh¹,

Reíter

2021

Antioxidants

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Biomolecular condensates are membraneless organelles (MLOs) that form dynamic, chemically distinct subcellular compartments organizing macromolecules such as proteins, RNA, and DNA in unicellular prokaryotic bacteria and complex eukaryotic cells. Separated from surrounding environments, MLOs in the nucleoplasm, cytoplasm, and mitochondria assemble by liquid–liquid phase separation (LLPS) into transient, non-static, liquid-like droplets that regulate essential molecular functions. LLPS is primarily controlled by post-translational modifications (PTMs) that fine-tune the balance between attractive and repulsive charge states and/or binding motifs of proteins. Aberrant phase separation due to dysregulated membrane lipid rafts and/or PTMs, as well as the absence of adequate hydrotropic small molecules such as ATP, or the presence of specific RNA proteins can cause pathological protein aggregation in neurodegenerative disorders. Melatonin may exert a dominant influence over phase separation in biomolecular condensates by optimizing membrane and MLO interdependent reactions through stabilizing lipid raft domains, reducing line tension, and maintaining negative membrane curvature and fluidity. As a potent antioxidant, melatonin protects cardiolipin and other membrane lipids from peroxidation cascades, supporting protein trafficking, signaling, ion channel activities, and ATPase functionality during condensate coacervation or dissolution. Melatonin may even control condensate LLPS through PTM and balance mRNA- and RNA-binding protein composition by regulating N6-methyladenosine (m6A) modifications. There is currently a lack of pharmaceuticals targeting neurodegenerative disorders via the regulation of phase separation. The potential of melatonin in the modulation of biomolecular condensate in the attenuation of aberrant condensate aggregation in neurodegenerative disorders is discussed in this review.

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“…1c, d). pT172 and the kinase that phosphorylates it, c-jun N-terminal kinase (JNK; [11][12][13]17],see also Additional file 2: Fig. S1b), were colocalized in the growth cone in both the C-and P-domains (Fig.…”

Section: Pt172 Of Gap-43 Is Detected In Growth Cones Of Cultured Mouse Neuronsmentioning

confidence: 99%

“…We have recently applied phosphoproteomics, a powerful technique to identify all phosphorylation sites of the proteome in a given system [10], to growth cone membranes derived from the rodent brain, and identified more than 1200 phospho-sites, most of which are not fully characterized [11][12][13]. Among these, phosphorylation of GAP-43 at S96, the top hit site, has been characterized and is tightly associated with axon growth and axon regeneration [11][12][13][14]. We identified another phosphorylation site of GAP-43, T172, in rodents.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of GAP-43 T172 is a molecular marker of growing axons in a wide range of mammals including primates

et al. 2021

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GAP-43 is a vertebrate neuron-specific protein and that is strongly related to axon growth and regeneration; thus, this protein has been utilized as a classical molecular marker of these events and growth cones. Although GAP-43 was biochemically characterized more than a quarter century ago, how this protein is related to these events is still not clear. Recently, we identified many phosphorylation sites in the growth cone membrane proteins of rodent brains. Two phosphorylation sites of GAP-43, S96 and T172, were found within the top 10 hit sites among all proteins. S96 has already been characterized (Kawasaki et al., 2018), and here, phosphorylation of T172 was characterized. In vitro (cultured neurons) and in vivo, an antibody specific to phosphorylated T172 (pT172 antibody) specifically recognized cultured growth cones and growing axons in developing mouse neurons, respectively. Immunoblotting showed that pT172 antigens were more rapidly downregulated throughout development than those of pS96 antibody. From the primary structure, this phosphorylation site was predicted to be conserved in a wide range of animals including primates. In the developing marmoset brainstem and in differentiated neurons derived from human induced pluripotent stem cells, immunoreactivity with pT172 antibody revealed patterns similar to those in mice. pT172 antibody also labeled regenerating axons following sciatic nerve injury. Taken together, the T172 residue is widely conserved in a wide range of mammals including primates, and pT172 is a new candidate molecular marker for growing axons.

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Neuronal Signaling Involved in Neuronal Polarization and Growth: Lipid Rafts and Phosphorylation

Cited by 22 publications

References 160 publications

One Raft to Guide Them All, and in Axon Regeneration Inhibit Them

One Raft to Guide Them All, and in Axon Regeneration Inhibit Them

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

Phosphorylation of GAP-43 T172 is a molecular marker of growing axons in a wide range of mammals including primates

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