Postsynaptic Y654 dephosphorylation of β-catenin modulates presynaptic vesicle turnover through increased n-cadherin-mediated transsynaptic signaling

2016 ◽  
Vol 77 (1) ◽  
pp. 61-74 ◽  
Author(s):  
Chin-Yi Chen ◽  
Yi-Ting Chen ◽  
Jen-Yeu Wang ◽  
Yi-Shuian Huang ◽  
Chin-Yin Tai
Keyword(s):  
Presynaptic Vesicle ◽  
Transsynaptic Signaling

scholarly journals A Discrete Presynaptic Vesicle Cycle for Neuromodulator Receptors

Neuron ◽  
2020 ◽  
Vol 105 (4) ◽  
pp. 663-677.e8 ◽  
Author(s):  
Damien Jullié ◽  
Miriam Stoeber ◽  
Jean-Baptiste Sibarita ◽  
Hanna L. Zieger ◽  
Thomas M. Bartol ◽  
...  
Keyword(s):  
Presynaptic Vesicle ◽  
Vesicle Cycle

scholarly journals Human autoantibodies to amphiphysin induce defective presynaptic vesicle dynamics and composition

Brain ◽  
2015 ◽  
Vol 139 (2) ◽  
pp. 365-379 ◽  
Author(s):  
Christian Werner ◽  
Martin Pauli ◽  
Sören Doose ◽  
Andreas Weishaupt ◽  
Holger Haselmann ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Ex Vivo ◽  
Super Resolution ◽  
Synaptic Activity ◽  
Stiff Person Syndrome ◽  
Specific Patient ◽  
Presynaptic Boutons ◽  
Presynaptic Vesicle

Abstract See Irani (doi:10.1093/awv364) for a scientific commentary on this article.  Stiff-person syndrome is the prototype of a central nervous system disorder with autoantibodies targeting presynaptic antigens. Patients with paraneoplastic stiff-person syndrome may harbour autoantibodies to the BAR (Bin/Amphiphysin/Rvs) domain protein amphiphysin, which target its SH3 domain. These patients have neurophysiological signs of compromised central inhibition and respond to symptomatic treatment with medication enhancing GABAergic transmission. High frequency neurotransmission as observed in tonic GABAergic interneurons relies on fast exocytosis of neurotransmitters based on compensatory endocytosis. As amphiphysin is involved in clathrin-mediated endocytosis, patient autoantibodies are supposed to interfere with this function, leading to disinhibition by reduction of GABAergic neurotransmission. We here investigated the effects of human anti-amphiphysin autoantibodies on structural components of presynaptic boutons ex vivo and in vitro using electron microscopy and super-resolution direct stochastic optical reconstruction microscopy. Ultrastructural analysis of spinal cord presynaptic boutons was performed after in vivo intrathecal passive transfer of affinity-purified human anti-amphiphysin autoantibodies in rats and revealed signs of markedly disabled clathrin-mediated endocytosis. This was unmasked at high synaptic activity and characterized by a reduction of the presynaptic vesicle pool, clathrin coated intermediates, and endosome-like structures. Super-resolution microscopy of inhibitory GABAergic presynaptic boutons in primary neurons revealed that specific human anti-amphiphysin immunoglobulin G induced an increase of the essential vesicular protein synaptobrevin 2 and a reduction of synaptobrevin 7. This constellation suggests depletion of resting pool vesicles and trapping of releasable pool vesicular proteins at the plasma membrane. Similar effects were found in amphiphysin-deficient neurons from knockout mice. Application of specific patient antibodies did not show additional effects. Blocking alternative pathways of clathrin-independent endocytosis with brefeldin A reversed the autoantibody induced effects on molecular vesicle composition. Endophilin as an interaction partner of amphiphysin showed reduced clustering within presynaptic terminals. Collectively, these results point towards an autoantibody-induced structural disorganization in GABAergic synapses with profound changes in presynaptic vesicle pools, activation of alternative endocytic pathways, and potentially compensatory rearrangement of proteins involved in clathrin-mediated endocytosis. Our findings provide novel insights into synaptic pathomechanisms in a prototypic antibody-mediated central nervous system disease, which may serve as a proof-of-principle example in this evolving group of autoimmune disorders associated with autoantibodies to synaptic antigens.

scholarly journals Tau interactome mapping reveals dynamic processes in synapses and mitochondria associated with neurodegenerative disease

2021 ◽  
Author(s):  
Tara E Tracy ◽  
Jesus Madero-Perez ◽  
Danielle Swaney ◽  
Timothy S Chang ◽  
Michelle Moritz ◽  
...  
Keyword(s):  
Affinity Purification ◽  
Induced Pluripotent Stem Cell ◽  
Proximity Ligation Assay ◽  
Spatiotemporal Resolution ◽  
Proximity Ligation ◽  
Cytosolic Domains ◽  
Presynaptic Vesicle ◽  
Underlying Mechanisms ◽  
Induced Pluripotent ◽  
Affinity Purification Mass Spectrometry

Tau (MAPT) drives neuronal dysfunction in Alzheimer's disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established activity-dependent interactions of Tau with presynaptic vesicle proteins during Tau secretion and mapped the exact APEX-tau-induced biotinylated tyrosines to the cytosolic domains of the interacting vesicular proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Tau's interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multi-modal and dynamic Tau interactomes with unprecedented spatiotemporal resolution shed novel insights into Tau's role in neuronal function and disease-related processes with potential therapeutic targets to block Tau-mediated pathogenesis.

scholarly journals Actomyosin-mediated nanostructural remodeling of the presynaptic vesicle pool by cannabinoids induces long-term depression

2018 ◽  
Author(s):  
Maureen H. McFadden ◽  
Hao Xu ◽  
Yihui Cui ◽  
Rebecca A. Piskorowski ◽  
Christophe Leterrier ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Receptor Activation ◽  
Synaptic Function ◽  
Actin Binding ◽  
Functional Plasticity ◽  
Structural Reorganization ◽  
Long Term Depression ◽  
Dynamic Regulation ◽  
Presynaptic Vesicle

AbstractEndo- and exocannabinoids, such as the psychoactive component of marijuana, exert their effects on brain function by inducing several forms of synaptic plasticity through the modulation of presynaptic vesicle release1-3. However, the molecular mechanisms underlying the widely expressed endocannabinoid-mediated long-term depression3 (eCB-LTD), are poorly understood. Here, we reveal that eCB-LTD depends on the contractile properties of the pre-synaptic actomyosin cytoskeleton. Preventing this contractility, both directly by inhibiting non-muscle myosin II NMII ATPase and indirectly by inhibiting the upstream Rho-associated kinase ROCK, abolished long-term, but not short-term forms of cannabinoid-induced functional plasticity in both inhibitory hippocampal and excitatory cortico-striatal synapses. Furthermore, using 3D superresolution microscopy, we find an actomyosin contractility-dependent redistribution of synaptic vesicle pools within the presynaptic compartment following cannabinoid receptor activation, leading to vesicle clustering and depletion from the pre-synaptic active zone. These results suggest that cannabinoid-induced functional plasticity is mediated by a nanoscale structural reorganization of the presynaptic compartment produced by actomyosin contraction. By introducing the contractile NMII as an important actin binding/structuring protein in the dynamic regulation of synaptic function, our results open new perspectives in the understanding of mechanisms of synaptic and cognitive function, marijuana intoxication and psychiatric pathogenesis.

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