scholarly journals Passive Transfer of Sera from ALS Patients with Identified Mutations Evokes an Increased Synaptic Vesicle Number and Elevation of Calcium Levels in Motor Axon Terminals, Similar to Sera from Sporadic Patients

2020 ◽  
Vol 21 (15) ◽  
pp. 5566
Author(s):  
Valéria Meszlényi ◽  
Roland Patai ◽  
Tamás F. Polgár ◽  
Bernát Nógrádi ◽  
Laura Körmöczy ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Intraperitoneal Injection ◽  
Passive Transfer ◽  
Synaptic Activity ◽  
Motor Axon ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Axon Terminals ◽  
Transgenic Mouse Strain ◽  
Low Incidence ◽  
Als Patients

Previously, we demonstrated increased calcium levels and synaptic vesicle densities in the motor axon terminals (MATs) of sporadic amyotrophic lateral sclerosis (ALS) patients. Such alterations could be conferred to mice with an intraperitoneal injection of sera from these patients or with purified immunoglobulin G. Later, we confirmed the presence of similar alterations in the superoxide dismutase 1 G93A transgenic mouse strain model of familial ALS. These consistent observations suggested that calcium plays a central role in the pathomechanism of ALS. This may be further reinforced by completing a similar analytical study of the MATs of ALS patients with identified mutations. However, due to the low yield of muscle biopsy samples containing MATs, and the low incidence of ALS patients with the identified mutations, these examinations are not technically feasible. Alternatively, a passive transfer of sera from ALS patients with known mutations was used, and the MATs of the inoculated mice were tested for alterations in their calcium homeostasis and synaptic activity. Patients with 11 different ALS-related mutations participated in the study. Intraperitoneal injection of sera from these patients on two consecutive days resulted in elevated intracellular calcium levels and increased vesicle densities in the MATs of mice, which is comparable to the effect of the passive transfer from sporadic patients. Our results support the idea that the pathomechanism underlying the identical manifestation of the disease with or without identified mutations is based on a common final pathway, in which increasing calcium levels play a central role.

The fate of foreign endplates in cross-innervated rat soleus muscle

1980 ◽  
Vol 208 (1171) ◽  
pp. 189-222 ◽  
Keyword(s):  
Muscle Fibre ◽  
Proximal Region ◽  
Presynaptic Terminal ◽  
Motor Axon ◽  
Muscle Fibres ◽  
Nerve Terminals ◽  
Axon Terminals ◽  
Adult Rat ◽  
Rat Soleus Muscle ◽  
Postsynaptic Site

After transplantation of the superficial fibular and the medial plantar nerve to neighbouring sites in the proximal region of adult rat soleus muscles many muscle fibres were initially innervated by axons in both foreign nerves after resection of the original soleus nerve. The foreign endplates were formed at ectopic sites and were often separately locatedon individual muscle fibres. After 3-4 weeks many endplates had been eliminated and most muscle fibres were innervated by only a single foreign axon. Many muscle fibres still had multiple esterase-staining endplate sites in the region innervated by the foreign nerve. On exami­nation by electronmicroscopy, some of these sites were seen to have lost their presynaptic terminal while the postsynaptic structure of the endplate remained intact. Other sites were only partially occupied by motor axon terminals. On each muscle fibre there was always at least one fully occupied endplate region. In some instances separate endplate sites on the same muscle fibre were innervated by branches of the same motor axon. We conclude that the elimination of endplates is due to a competitive interaction between motor axons innervating the same muscle fibre. Morphologically, the elimination of functional endplates is caused by a retraction of nerve terminals from the postsynaptic site.

Form and classification of motor endings in mammalian muscle spindles

1985 ◽  
Vol 225 (1239) ◽  
pp. 195-212 ◽  
Keyword(s):  
Muscle Fibre ◽  
Fibre Type ◽  
Muscle Spindles ◽  
Muscle Fibre Type ◽  
Motor Axon ◽  
Muscle Fibres ◽  
Intrafusal Muscle ◽  
Axon Terminals ◽  
Hindlimb Muscle

The presynaptic features of 234 motor endings supplied to cat hindlimb muscle spindles have been studied in teased, silver preparations, and the postsynaptic features of a further 27 endings have been studied in serial, 1 μm thick, transverse sections. In the presynaptic study motor endings received by the three types of intrafusal muscle fibre were compared with the endings supplied to spindles by the various functional categories of motor axon. Three forms of motor ending were found that had significantly different presynaptic features. These forms correspond closely to those previously identified in the literature as p 1 (β), p 2 (dynamic γ) and trail (static γ). The results of the postsynaptic study showed that the degree of indentation of the intrafusal muscle fibres by motor axon terminals increases with greater distance from the primary ending, irrespective of muscle-fibre type. We conclude that the postsynaptic form of intrafusal motor endings is determined by distance from primary ending and muscle-fibre type. It is not determined by type of motor axon, and cannot be correlated with presynaptic form so as to produce a unified classification of intrafusal motor endings.

scholarly journals An Agonist of the CXCR4 Receptor Strongly Promotes Regeneration of Degenerated Motor Axon Terminals

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1183 ◽  
Author(s):  
Negro ◽  
Zanetti ◽  
Mattarei ◽  
Valentini ◽  
Megighian ◽  
...  
Keyword(s):  
Functional Recovery ◽  
Neuromuscular Junctions ◽  
Recovery Of Function ◽  
Motor Axon ◽  
Cxcr4 Antagonist ◽  
Axon Terminals ◽  
Stem Cell Migration ◽  
Natural Ligand ◽  
Nerve Recovery ◽  
Strong Candidate

The activation of the G-protein coupled receptor CXCR4 by its ligand CXCL12α is involved in a large variety of physiological and pathological processes, including the growth of B cells precursors and of motor axons, autoimmune diseases, stem cell migration, inflammation, and several neurodegenerative conditions. Recently, we demonstrated that CXCL12α potently stimulates the functional recovery of damaged neuromuscular junctions via interaction with CXCR4. This result prompted us to test the neuroregeneration activity of small molecules acting as CXCR4 agonists, endowed with better pharmacokinetics with respect to the natural ligand. We focused on NUCC-390, recently shown to activate CXCR4 in a cellular system. We designed a novel and convenient chemical synthesis of NUCC-390, which is reported here. NUCC-390 was tested for its capability to induce the regeneration of motor axon terminals completely degenerated by the presynaptic neurotoxin α-Latrotoxin. NUCC-390 was found to strongly promote the functional recovery of the neuromuscular junction, as assayed by electrophysiology and imaging. This action is CXCR4 dependent, as it is completely prevented by AMD3100, a well-characterized CXCR4 antagonist. These data make NUCC-390 a strong candidate to be tested in human therapy to promote nerve recovery of function after different forms of neurodegeneration.

scholarly journals Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model

2022 ◽  
Vol 5 (4) ◽  
pp. e202101193
Author(s):  
Megumi Akamatsu ◽  
Takenari Yamashita ◽  
Sayaka Teramoto ◽  
Zhen Huang ◽  
Janet Lynch ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Motor Neurons ◽  
Ampa Receptors ◽  
Motor Dysfunction ◽  
Rna Aptamers ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Efficacy And Safety ◽  
Intracerebroventricular Infusion ◽  
Sporadic Als ◽  
Als Patients

In motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients, the RNA editing at the glutamine/arginine site of the GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors is defective or incomplete. As a result, AMPA receptors containing the abnormally expressed, unedited isoform of GluA2 are highly Ca2+-permeable, and are responsible for mediating abnormal Ca2+ influx, thereby triggering motor neuron degeneration and cell death. Thus, blocking the AMPA receptor–mediated, abnormal Ca2+ influx is a potential therapeutic strategy for treatment of sporadic ALS. Here, we report a study of the efficacy and safety of two RNA aptamers targeting AMPA receptors on the ALS phenotype of AR2 mice. A 12-wk continuous, intracerebroventricular infusion of aptamers to AR2 mice reduced the progression of motor dysfunction, normalized TDP-43 mislocalization, and prevented death of motor neurons. Our results demonstrate that the use of AMPA receptor aptamers as a novel class of AMPA receptor antagonists is a promising strategy for developing an ALS treatment approach.

scholarly journals A dynamin 1-, dynamin 3- and clathrin-independent pathway of synaptic vesicle recycling mediated by bulk endocytosis

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Yumei Wu ◽  
Eileen T O'Toole ◽  
Martine Girard ◽  
Brigitte Ritter ◽  
Mirko Messa ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Synaptic Vesicles ◽  
Synaptic Activity ◽  
Synaptic Vesicle Recycling ◽  
Knock Out ◽  
Knock Down ◽  
Vesicle Recycling ◽  
Subsequent Conversion ◽  
Insight Into

The exocytosis of synaptic vesicles (SVs) elicited by potent stimulation is rapidly compensated by bulk endocytosis of SV membranes leading to large endocytic vacuoles (‘bulk’ endosomes). Subsequently, these vacuoles disappear in parallel with the reappearance of new SVs. We have used synapses of dynamin 1 and 3 double knock-out neurons, where clathrin-mediated endocytosis (CME) is dramatically impaired, to gain insight into the poorly understood mechanisms underlying this process. Massive formation of bulk endosomes was not defective, but rather enhanced, in the absence of dynamin 1 and 3. The subsequent conversion of bulk endosomes into SVs was not accompanied by the accumulation of clathrin coated buds on their surface and this process proceeded even after further clathrin knock-down, suggesting its independence of clathrin. These findings support the existence of a pathway for SV reformation that bypasses the requirement for clathrin and dynamin 1/3 and that operates during intense synaptic activity.

scholarly journals TDP-43 is intercellularly transmitted across axon terminals

2015 ◽  
Vol 211 (4) ◽  
pp. 897-911 ◽  
Author(s):  
Marisa S. Feiler ◽  
Benjamin Strobel ◽  
Axel Freischmidt ◽  
Anika M. Helferich ◽  
Julia Kappel ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Dna Binding Protein ◽  
Neuronal Cultures ◽  
Axon Terminals ◽  
Intracellular Aggregates ◽  
Protein Complementation ◽  
Als Patients ◽  
Cell Somata ◽  
Lateral Sclerosis ◽  
Novel Protein

Transactive response DNA-binding protein 43 kD (TDP-43) is an aggregation-prone prion-like domain-containing protein and component of pathological intracellular aggregates found in most amyotrophic lateral sclerosis (ALS) patients. TDP-43 oligomers have been postulated to be released and subsequently nucleate TDP-43 oligomerization in recipient cells, which might be the molecular correlate of the systematic symptom spreading observed during ALS progression. We developed a novel protein complementation assay allowing quantification of TDP-43 oligomers in living cells. We demonstrate the exchange of TDP-43 between cell somata and the presence of TDP-43 oligomers in microvesicles/exosomes and show that microvesicular TDP-43 is preferentially taken up by recipient cells where it exerts higher toxicity than free TDP-43. Moreover, studies using microfluidic neuronal cultures suggest both anterograde and retrograde trans-synaptic spreading of TDP-43. Finally, we demonstrate TDP-43 oligomer seeding by TDP-43–containing material derived from both cultured cells and ALS patient brain lysate. Thus, using an innovative detection technique, we provide evidence for preferentially microvesicular uptake as well as both soma-to-soma “horizontal” and bidirectional “vertical” synaptic intercellular transmission and prion-like seeding of TDP-43.

scholarly journals CXCL 12α/ SDF ‐1 from perisynaptic Schwann cells promotes regeneration of injured motor axon terminals

2017 ◽  
Vol 9 (8) ◽  
pp. 1000-1010 ◽  
Author(s):  
Samuele Negro ◽  
Francesca Lessi ◽  
Elisa Duregotti ◽  
Paolo Aretini ◽  
Marco La Ferla ◽  
...  
Keyword(s):  
Schwann Cells ◽  
Motor Axon ◽  
Axon Terminals ◽  
Perisynaptic Schwann Cells

scholarly journals Inactivation of clathrin heavy chain inhibits synaptic recycling but allows bulk membrane uptake

2008 ◽  
Vol 182 (5) ◽  
pp. 1007-1016 ◽  
Author(s):  
Jaroslaw Kasprowicz ◽  
Sabine Kuenen ◽  
Katarzyna Miskiewicz ◽  
Ron L.P. Habets ◽  
Liesbet Smitz ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Heavy Chain ◽  
Synaptic Activity ◽  
Synaptic Membrane ◽  
Vesicle Recycling ◽  
Clathrin Heavy Chain ◽  
Early Embryonic Lethality ◽  
Bulk Membrane ◽  
Multicellular Organisms

Synaptic vesicle reformation depends on clathrin, an abundant protein that polymerizes around newly forming vesicles. However, how clathrin is involved in synaptic recycling in vivo remains unresolved. We test clathrin function during synaptic endocytosis using clathrin heavy chain (chc) mutants combined with chc photoinactivation to circumvent early embryonic lethality associated with chc mutations in multicellular organisms. Acute inactivation of chc at stimulated synapses leads to substantial membrane internalization visualized by live dye uptake and electron microscopy. However, chc-inactivated membrane cannot recycle and participate in vesicle release, resulting in a dramatic defect in neurotransmission maintenance during intense synaptic activity. Furthermore, inactivation of chc in the context of other endocytic mutations results in membrane uptake. Our data not only indicate that chc is critical for synaptic vesicle recycling but they also show that in the absence of the protein, bulk retrieval mediates massive synaptic membrane internalization.

scholarly journals Aberrant Morphology and Residual Transmitter Release at the Munc13-Deficient Mouse Neuromuscular Synapse

2005 ◽  
Vol 25 (14) ◽  
pp. 5973-5984 ◽  
Author(s):  
Frédérique Varoqueaux ◽  
Michèle S. Sons ◽  
Jaap J. Plomp ◽  
Nils Brose
Keyword(s):  
Neuromuscular Junction ◽  
Synaptic Vesicle ◽  
Motor Neurons ◽  
Transmitter Release ◽  
Hippocampal Neurons ◽  
Neuromuscular Junctions ◽  
Neuromuscular Synapse ◽  
Synaptic Activity ◽  
Neuromuscular Synaptogenesis ◽  
Deficient Mice

ABSTRACT In cultured hippocampal neurons, synaptogenesis is largely independent of synaptic transmission, while several accounts in the literature indicate that synaptogenesis at cholinergic neuromuscular junctions in mammals appears to partially depend on synaptic activity. To systematically examine the role of synaptic activity in synaptogenesis at the neuromuscular junction, we investigated neuromuscular synaptogenesis and neurotransmitter release of mice lacking all synaptic vesicle priming proteins of the Munc13 family. Munc13-deficient mice are completely paralyzed at birth and die immediately, but form specialized neuromuscular endplates that display typical synaptic features. However, the distribution, number, size, and shape of these synapses, as well as the number of motor neurons they originate from and the maturation state of muscle cells, are profoundly altered. Surprisingly, Munc13-deficient synapses exhibit significantly increased spontaneous quantal acetylcholine release, although fewer fusion-competent synaptic vesicles are present and nerve stimulation-evoked secretion is hardly elicitable and strongly reduced in magnitude. We conclude that the residual transmitter release in Munc13-deficient mice is not sufficient to sustain normal synaptogenesis at the neuromuscular junction, essentially causing morphological aberrations that are also seen upon total blockade of neuromuscular transmission in other genetic models. Our data confirm the importance of Munc13 proteins in synaptic vesicle priming at the neuromuscular junction but indicate also that priming at this synapse may differ from priming at glutamatergic and γ-aminobutyric acid-ergic synapses and is partly Munc13 independent. Thus, non-Munc13 priming proteins exist at this synapse or vesicle priming occurs in part spontaneously: i.e., without dedicated priming proteins in the release machinery.

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