Type IIa RPTPs and Glycans: Roles in Axon Regeneration and Synaptogenesis

Type IIa receptor tyrosine phosphatases (RPTPs) play pivotal roles in neuronal network formation. It is emerging that the interactions of RPTPs with glycans, i.e., chondroitin sulfate (CS) and heparan sulfate (HS), are critical for their functions. We highlight here the significance of these interactions in axon regeneration and synaptogenesis. For example, PTPσ, a member of type IIa RPTPs, on axon terminals is monomerized and activated by the extracellular CS deposited in neural injuries, dephosphorylates cortactin, disrupts autophagy flux, and consequently inhibits axon regeneration. In contrast, HS induces PTPσ oligomerization, suppresses PTPσ phosphatase activity, and promotes axon regeneration. PTPσ also serves as an organizer of excitatory synapses. PTPσ and neurexin bind one another on presynapses and further bind to postsynaptic leucine-rich repeat transmembrane protein 4 (LRRTM4). Neurexin is now known as a heparan sulfate proteoglycan (HSPG), and its HS is essential for the binding between these three molecules. Another HSPG, glypican 4, binds to presynaptic PTPσ and postsynaptic LRRTM4 in an HS-dependent manner. Type IIa RPTPs are also involved in the formation of excitatory and inhibitory synapses by heterophilic binding to a variety of postsynaptic partners. We also discuss the important issue of possible mechanisms coordinating axon extension and synapse formation.

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Harnessing PTEN’s Growth Potential in Neuronal Development and Disease

Neuroscience Insights ◽

10.1177/2633105520959056 ◽

2020 ◽

Vol 15 ◽

pp. 263310552095905

Author(s):

Joachim Fuchs ◽

Britta J. Eickholt ◽

George Leondaritis

Keyword(s):

Neurodevelopmental Disorders ◽

Neuronal Development ◽

System Development ◽

Transmembrane Protein ◽

Nervous System Development ◽

Growth Potential ◽

Dependent Manner ◽

Axon Extension ◽

Growth Promoting ◽

Spatiotemporal Control

PTEN is a powerful regulator of neuronal growth. It globally suppresses axon extension and branching during both nervous system development and regeneration, by antagonizing growth-promoting PI3K/PI(3,4,5)P3 signaling. We recently identified that the transmembrane protein PRG2/LPPR3 functions as a modulator of PTEN function during axon morphogenesis. Our work demonstrates that through inhibition of PTEN activity, PRG2 stabilizes membrane PI(3,4,5)P3. In turn, PRG2 deficiency attenuates the formation of branches in a PTEN-dependent manner, albeit without affecting the overall growth capacity of extending axons. Thus, PRG2 is poised to temporally and locally relieve growth suppression mediated by PTEN in neurons and, in effect, to redirect growth specifically to axonal branches. In this commentary, we discuss potential implications and unresolved questions regarding the regulation of axonal PTEN in neurons. Given their widespread implication during neuronal development and regeneration, identification of mechanisms that confer spatiotemporal control of PTEN may unveil new approaches to reprogram PI3K signaling in neurodevelopmental disorders and regeneration research.

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Development of Presynaptic Inhibition Onto Retinal Bipolar Cell Axon Terminals Is Subclass-Specific

Journal of Neurophysiology ◽

10.1152/jn.90202.2008 ◽

2008 ◽

Vol 100 (1) ◽

pp. 304-316 ◽

Cited By ~ 35

Author(s):

Timm Schubert ◽

Daniel Kerschensteiner ◽

Erika D. Eggers ◽

Thomas Misgeld ◽

Martin Kerschensteiner ◽

...

Keyword(s):

Bipolar Cell ◽

Presynaptic Inhibition ◽

Synapse Formation ◽

Critical Role ◽

Bipolar Cells ◽

Inhibitory Synapses ◽

Axon Terminals ◽

Cell Recording ◽

Retinal Bipolar Cells ◽

Cone Bipolar Cells

Synaptic integration is modulated by inhibition onto the dendrites of postsynaptic cells. However, presynaptic inhibition at axonal terminals also plays a critical role in the regulation of neurotransmission. In contrast to the development of inhibitory synapses onto dendrites, GABAergic/glycinergic synaptogenesis onto axon terminals has not been widely studied. Because retinal bipolar cells receive subclass-specific patterns of GABAergic and glycinergic presynaptic inhibition, they are a good model for studying the development of inhibition at axon terminals. Here, using whole cell recording methods and transgenic mice in which subclasses of retinal bipolar cells are labeled, we determined the temporal sequence and patterning of functional GABAergic and glycinergic input onto the major subclasses of bipolar cells. We found that the maturation of GABAergic and glycinergic synapses onto the axons of rod bipolar cells (RBCs), on-cone bipolar cells (on-CBCs) and off-cone bipolar cells (off-CBCs) were temporally distinct: spontaneous chloride-mediated currents are present in RBCs earlier in development compared with on- and off-CBC, and RBCs receive GABAergic and glycinergic input simultaneously, whereas in off-CBCs, glycinergic transmission emerges before GABAergic transmission. Because on-CBCs show little inhibitory activity, GABAergic and glycinergic events could not be pharmacologically distinguished for these bipolar cells. The balance of GABAergic and glycinergic input that is unique to RBCs and off-CBCs is established shortly after the onset of synapse formation and precedes visual experience. Our data suggest that presynaptic modulation of glutamate transmission from bipolar cells matures rapidly and is differentially coordinated for GABAergic and glycinergic synapses onto distinct bipolar cell subclasses.

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Sushi domain-containing protein 4 controls synaptic plasticity and motor learning

eLife ◽

10.7554/elife.65712 ◽

2021 ◽

Vol 10 ◽

Author(s):

Inés González-Calvo ◽

Keerthana Iyer ◽

Mélanie Carquin ◽

Anouar Khayachi ◽

Fernando A Giuliani ◽

...

Keyword(s):

Ampa Receptor ◽

Motor Coordination ◽

Synapse Formation ◽

Transmembrane Protein ◽

Dependent Manner ◽

Loss Of Function ◽

Neuronal Populations ◽

Ampa Receptor Subunit ◽

Fine Control ◽

Activity Dependent

Fine control of protein stoichiometry at synapses underlies brain function and plasticity. How proteostasis is controlled independently for each type of synaptic protein in a synapse-specific and activity-dependent manner remains unclear. Here, we show that Susd4, a gene coding for a complement-related transmembrane protein, is expressed by many neuronal populations starting at the time of synapse formation. Constitutive loss-of-function of Susd4 in the mouse impairs motor coordination adaptation and learning, prevents long-term depression at cerebellar synapses, and leads to misregulation of activity-dependent AMPA receptor subunit GluA2 degradation. We identified several proteins with known roles in the regulation of AMPA receptor turnover, in particular ubiquitin ligases of the NEDD4 subfamily, as SUSD4 binding partners. Our findings shed light on the potential role of SUSD4 mutations in neurodevelopmental diseases.

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PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1410138112 ◽

2015 ◽

Vol 112 (6) ◽

pp. 1874-1879 ◽

Cited By ~ 55

Author(s):

Ji Seung Ko ◽

Gopal Pramanik ◽

Ji Won Um ◽

Ji Seon Shim ◽

Dongmin Lee ◽

...

Keyword(s):

Synaptic Transmission ◽

Synapse Formation ◽

Transmembrane Protein ◽

Protein Tyrosine Phosphatases ◽

Excitatory Synaptic Transmission ◽

Receptor Protein ◽

Synapse Development ◽

Dependent Manner ◽

And Function ◽

Receptor Protein Tyrosine Phosphatases

Leukocyte common antigen-related receptor protein tyrosine phosphatases—comprising LAR, PTPδ, and PTPσ—are synaptic adhesion molecules that organize synapse development. Here, we identify glypican 4 (GPC-4) as a ligand for PTPσ. GPC-4 showed strong (nanomolar) affinity and heparan sulfate (HS)-dependent interaction with the Ig domains of PTPσ. PTPσ bound only to proteolytically cleaved GPC-4 and formed additional complex with leucine-rich repeat transmembrane protein 4 (LRRTM4) in rat brains. Moreover, single knockdown (KD) of PTPσ, but not LAR, in cultured neurons significantly reduced the synaptogenic activity of LRRTM4, a postsynaptic ligand of GPC-4, in heterologous synapse-formation assays. Finally, PTPσ KD dramatically decreased both the frequency and amplitude of excitatory synaptic transmission. This effect was reversed by wild-type PTPσ, but not by a HS-binding–defective PTPσ mutant. Our results collectively suggest that presynaptic PTPσ, together with GPC-4, acts in a HS-dependent manner to maintain excitatory synapse development and function.

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Glypicans and Heparan Sulfate in Synaptic Development, Neural Plasticity, and Neurological Disorders

Frontiers in Neural Circuits ◽

10.3389/fncir.2021.595596 ◽

2021 ◽

Vol 15 ◽

Author(s):

Keisuke Kamimura ◽

Nobuaki Maeda

Keyword(s):

Heparan Sulfate ◽

Neural Plasticity ◽

Neurological Disorders ◽

Network Formation ◽

Synapse Formation ◽

Protein Tyrosine Phosphatases ◽

Autism Spectrum ◽

Bmp Signaling ◽

Receptor Protein ◽

Core Proteins

Heparan sulfate proteoglycans (HSPGs) are components of the cell surface and extracellular matrix, which bear long polysaccharides called heparan sulfate (HS) attached to the core proteins. HSPGs interact with a variety of ligand proteins through the HS chains, and mutations in HSPG-related genes influence many biological processes and cause various diseases. In particular, recent findings from vertebrate and invertebrate studies have raised the importance of glycosylphosphatidylinositol-anchored HSPGs, glypicans, as central players in the development and functions of synapses. Glypicans are important components of the synapse-organizing protein complexes and serve as ligands for leucine-rich repeat transmembrane neuronal proteins (LRRTMs), leukocyte common antigen-related (LAR) family receptor protein tyrosine phosphatases (RPTPs), and G-protein-coupled receptor 158 (GPR158), regulating synapse formation. Many of these interactions are mediated by the HS chains of glypicans. Neurexins (Nrxs) are also synthesized as HSPGs and bind to some ligands in common with glypicans through HS chains. Therefore, glypicans and Nrxs may act competitively at the synapses. Furthermore, glypicans regulate the postsynaptic expression levels of ionotropic glutamate receptors, controlling the electrophysiological properties and non-canonical BMP signaling of synapses. Dysfunctions of glypicans lead to failures in neuronal network formation, malfunction of synapses, and abnormal behaviors that are characteristic of neurodevelopmental disorders. Recent human genetics revealed that glypicans and HS are associated with autism spectrum disorder, neuroticism, and schizophrenia. In this review, we introduce the studies showing the roles of glypicans and HS in synapse formation, neural plasticity, and neurological disorders, especially focusing on the mouse and Drosophila as potential models for human diseases.

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Neuroligin-2 as a central organizer of inhibitory synapses in health and disease

Science Signaling ◽

10.1126/scisignal.abd8379 ◽

2020 ◽

Vol 13 (663) ◽

pp. eabd8379

Author(s):

Heba Ali ◽

Lena Marth ◽

Dilja Krueger-Burg

Keyword(s):

Synaptic Transmission ◽

Synapse Formation ◽

Current Knowledge ◽

Protein Complexes ◽

Inhibitory Synapses ◽

Molecular Architecture ◽

Cellular Functions ◽

Altered Expression ◽

Health And Disease ◽

Flow Of Information

Postsynaptic organizational protein complexes play central roles both in orchestrating synapse formation and in defining the functional properties of synaptic transmission that together shape the flow of information through neuronal networks. A key component of these organizational protein complexes is the family of synaptic adhesion proteins called neuroligins. Neuroligins form transsynaptic bridges with presynaptic neurexins to regulate various aspects of excitatory and inhibitory synaptic transmission. Neuroligin-2 (NLGN2) is the only member that acts exclusively at GABAergic inhibitory synapses. Altered expression and mutations in NLGN2 and several of its interacting partners are linked to cognitive and psychiatric disorders, including schizophrenia, autism, and anxiety. Research on NLGN2 has fundamentally shaped our understanding of the molecular architecture of inhibitory synapses. Here, we discuss the current knowledge on the molecular and cellular functions of mammalian NLGN2 and its role in the neuronal circuitry that regulates behavior in rodents and humans.

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Specific heparan sulfate modifications stabilize the synaptic organizer MADD-4/Punctin at C. elegans neuromuscular junctions

Genetics ◽

10.1093/genetics/iyab073 ◽

2021 ◽

Author(s):

Mélissa Cizeron ◽

Laure Granger ◽

Hannes E BÜlow ◽

Jean-Louis Bessereau

Keyword(s):

Heparan Sulfate ◽

Matrix Protein ◽

Neuromuscular Junctions ◽

Core Protein ◽

Extracellular Matrix Protein ◽

Inhibitory Synapses ◽

Single Chain ◽

C Elegans ◽

Sugar Chains

Abstract Heparan sulfate proteoglycans contribute to the structural organization of various neurochemical synapses. Depending on the system, their role involves either the core protein or the glycosaminoglycan chains. These linear sugar chains are extensively modified by heparan sulfate modification enzymes, resulting in highly diverse molecules. Specific modifications of glycosaminoglycan chains may thus contribute to a sugar code involved in synapse specificity. Caenorhabditis elegans is particularly useful to address this question because of the low level of genomic redundancy of these enzymes, as opposed to mammals. Here, we systematically mutated the genes encoding heparan sulfate modification enzymes in C. elegans and analyzed their impact on excitatory and inhibitory neuromuscular junctions. Using single chain antibodies that recognize different heparan sulfate modification patterns, we show in vivo that these two heparan sulfate epitopes are carried by the SDN-1 core protein, the unique C. elegans syndecan orthologue, at neuromuscular junctions. Intriguingly, these antibodies differentially bind to excitatory and inhibitory synapses, implying unique heparan sulfate modification patterns at different neuromuscular junctions. Moreover, while most enzymes are individually dispensable for proper organization of neuromuscular junctions, we show that 3-O-sulfation of SDN-1 is required to maintain wild-type levels of the extracellular matrix protein MADD-4/Punctin, a central synaptic organizer that defines the identity of excitatory and inhibitory synaptic domains at the plasma membrane of muscle cells.

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The EF-Hand Ca2+-binding Protein p22 Plays a Role in Microtubule and Endoplasmic Reticulum Organization and Dynamics with Distinct Ca2+-binding Requirements

Molecular Biology of the Cell ◽

10.1091/mbc.e03-07-0500 ◽

2004 ◽

Vol 15 (2) ◽

pp. 481-496 ◽

Cited By ~ 34

Author(s):

Josefa Andrade ◽

Hu Zhao ◽

Brian Titus ◽

Sandra Timm Pearce ◽

Margarida Barroso

Keyword(s):

Endoplasmic Reticulum ◽

Conformational Changes ◽

Membrane Trafficking ◽

Secretory Pathway ◽

Network Formation ◽

Binding Protein ◽

Dependent Manner ◽

Microtubule Depolymerization ◽

Independent Manner ◽

Ef Hand

We have reported that p22, an N-myristoylated EF-hand Ca2+-binding protein, associates with microtubules and plays a role in membrane trafficking. Here, we show that p22 also associates with membranes of the early secretory pathway membranes, in particular endoplasmic reticulum (ER). On binding of Ca2+, p22's ability to associate with membranes increases in an N-myristoylation-dependent manner, which is suggestive of a nonclassical Ca2+-myristoyl switch mechanism. To address the intracellular functions of p22, a digitonin-based “bulk microinjection” assay was developed to load cells with anti-p22, wild-type, or mutant p22 proteins. Antibodies against a p22 peptide induce microtubule depolymerization and ER fragmentation; this antibody-mediated effect is overcome by preincubation with the respective p22 peptide. In contrast, N-myristoylated p22 induces the formation of microtubule bundles, the accumulation of ER structures along the bundles as well as an increase in ER network formation. An N-myristoylated Ca2+-binding p22 mutant, which is unable to undergo Ca2+-mediated conformational changes, induces microtubule bundling and accumulation of ER structures along the bundles but does not increase ER network formation. Together, these data strongly suggest that p22 modulates the organization and dynamics of microtubule cytoskeleton in a Ca2+-independent manner and affects ER network assembly in a Ca2+-dependent manner.

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Age-dependent formation of TMEM106B amyloid filaments in human brain

10.1101/2021.11.09.467923 ◽

2021 ◽

Author(s):

Manuel Schweighauser ◽

Diana Arseni ◽

Melissa Huang ◽

Sofia Lövestam ◽

Yang Shi ◽

...

Keyword(s):

Human Brain ◽

Transmembrane Protein ◽

Amyloid Β ◽

Dependent Manner ◽

Type Ii ◽

Western Blots ◽

Normal Individuals ◽

Age Dependent ◽

Neurologically Normal ◽

Filamentous Inclusions

Many age-dependent neurodegenerative diseases, like Alzheimer's and Parkinson's, are characterised by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β (Aβ), α-synuclein and TDP-43 are the most common. Here, we used electron cryo-microscopy (cryo-EM) structure determination to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in the human brain. We solved cryo-EM structures of TMEM106B filaments from the brains of 22 individuals with neurodegenerative conditions, including sporadic and inherited tauopathies, Aβ-amyloidoses, synucleinopathies and TDP-43opathies, as well as from the brains of two neurologically normal individuals. We observed three different TMEM106B folds, with no clear relationship between folds and diseases. The presence of TMEM106B filaments correlated with that of a 29 kDa sarkosyl-insoluble fragment of the protein on Western blots. The presence of TMEM106B filaments in the brains of older, but not younger, neurologically normal individuals indicates that they form in an age-dependent manner.

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Aberrant information transfer interferes with functional axon regeneration

eLife ◽

10.7554/elife.38829 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 3

Author(s):

Chen Ding ◽

Marc Hammarlund

Keyword(s):

Information Transfer ◽

Synapse Formation ◽

Axon Regeneration ◽

Behavioral Recovery ◽

Axon Injury ◽

Functional Regeneration ◽

Key Variables ◽

And Function ◽

Circuit Function ◽

Molecular Components

Functional axon regeneration requires regenerating neurons to restore appropriate synaptic connectivity and circuit function. To model this process, we developed an assay in Caenorhabditis elegans that links axon and synapse regeneration of a single neuron to recovery of behavior. After axon injury and regeneration of the DA9 neuron, synapses reform at their pre-injury location. However, these regenerated synapses often lack key molecular components. Further, synaptic vesicles accumulate in the dendrite in response to axon injury. Dendritic vesicle release results in information misrouting that suppresses behavioral recovery. Dendritic synapse formation depends on dynein and jnk-1. But even when information transfer is corrected, axonal synapses fail to adequately transmit information. Our study reveals unexpected plasticity during functional regeneration. Regeneration of the axon is not sufficient for the reformation of correct neuronal circuits after injury. Rather, synapse reformation and function are also key variables, and manipulation of circuit reformation improves behavioral recovery.

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