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Neural Regeneration Research Jul 2024α-Synuclein is a protein that mainly exists in the presynaptic terminals. Abnormal folding and accumulation of α-synuclein are found in several neurodegenerative...
α-Synuclein is a protein that mainly exists in the presynaptic terminals. Abnormal folding and accumulation of α-synuclein are found in several neurodegenerative diseases, including Parkinson's disease. Aggregated and highly phosphorylated α-synuclein constitutes the main component of Lewy bodies in the brain, the pathological hallmark of Parkinson's disease. For decades, much attention has been focused on the accumulation of α-synuclein in the brain parenchyma rather than considering Parkinson's disease as a systemic disease. Recent evidence demonstrates that, at least in some patients, the initial α-synuclein pathology originates in the peripheral organs and spreads to the brain. Injection of α-synuclein preformed fibrils into the gastrointestinal tract triggers the gut-to-brain propagation of α-synuclein pathology. However, whether α-synuclein pathology can occur spontaneously in peripheral organs independent of exogenous α-synuclein preformed fibrils or pathological α-synuclein leakage from the central nervous system remains under investigation. In this review, we aimed to summarize the role of peripheral α-synuclein pathology in the pathogenesis of Parkinson's disease. We also discuss the pathways by which α-synuclein pathology spreads from the body to the brain.
PubMed: 38051888
DOI: 10.4103/1673-5374.387967 -
Scientific Reports Sep 2023F-FP-CIT is a high-resolution imaging marker of nigrostriatal neuronal integrity, differentiating Parkinsonism with loss of dopaminergic terminals (presynaptic...
F-FP-CIT is a high-resolution imaging marker of nigrostriatal neuronal integrity, differentiating Parkinsonism with loss of dopaminergic terminals (presynaptic Parkinsonian syndrome [PS]) from Parkinsonism without nigrostriatal degeneration (non-PS). We assessed the diagnostic accuracy of F-FP-CIT PET in patients with clinically uncertain PS (CUPS) at the first visit. Among the 272 patients who underwent F-FP-CIT PET imaging at the first visit between September 2008 and July 2012, 111 had CUPS (age, 62.6 ± 10.5 y; male:female, 45:66; symptom duration, 13.1 ± 8.8 months). Uncertainty criteria included only one of the three cardinal signs of Parkinsonism, two signs without bradykinesia, or atypical signs. The baseline clinical and F-FP-CIT PET imaging diagnostic accuracy was compared with the accuracy of clinical diagnosis after > 2-year follow-up. Nuclear medicine physicians assessed the F-FP-CIT PET images visually. Focal dopamine transporter binding deficit in the posterior putamen was considered PS. Bilateral symmetric striatum without focal deficit, suggesting normal F-FP-CIT PET, and focal deficits elsewhere in the striatum suggesting vascular Parkinsonism were considered non-PS. Seventy-nine patients had PS, and 32 did not. Baseline clinical diagnosis included PS in 45 patients, non-PS in 24, and inconclusive in 42. Among patients in whom initial clinical diagnosis (PS or non-PS) was possible, the sensitivity, specificity, and accuracy of the baseline clinical and F-FP-CIT PET imaging diagnoses were 54.4, 50.0, and 53.2%, and 98.7, 100, and 99.1%, respectively. The respective positive and negative predictive values were 95.6 and 66.7%, and 100 and 97.0%. Among those with initially inconclusive diagnosis, 64.2% were eventually diagnosed with PS while 35.7% were diagnosed with non-PS. The final clinical diagnosis of these patients all matched those made by F-FP-CIT PET imaging, except in one patient with scan without evidence of dopaminergic deficit (SWEDD). F-FP-CIT PET diagnosis was more accurate than clinical diagnosis, reducing the false-negative and inconclusive clinical diagnosis rates at baseline in patients with CUPS.
Topics: Humans; Female; Male; Middle Aged; Aged; Uncertainty; Parkinsonian Disorders; Parkinson Disease, Secondary; Dopamine; Positron-Emission Tomography
PubMed: 37700061
DOI: 10.1038/s41598-023-42135-9 -
BioRxiv : the Preprint Server For... Mar 2024One of the most extensively studied members of the Ras superfamily of small GTPases, Rac1 is an intracellular signal transducer that remodels actin and phosphorylation...
One of the most extensively studied members of the Ras superfamily of small GTPases, Rac1 is an intracellular signal transducer that remodels actin and phosphorylation signaling networks. Previous studies have shown that Rac1-mediated signaling is associated with hippocampal-dependent working memory and longer-term forms of learning and memory and that Rac1 can modulate forms of both pre- and postsynaptic plasticity. How these different cognitive functions and forms of plasticity mediated by Rac1 are linked, however, is unclear. Here, we show that spatial working memory is selectively impaired following the expression of a genetically encoded Rac1-inhibitor at presynaptic terminals, while longer-term cognitive processes are affected by Rac1 inhibition at postsynaptic sites. To investigate the regulatory mechanisms of this presynaptic process, we leveraged new advances in mass spectrometry to identify the proteomic and post-translational landscape of presynaptic Rac1 signaling. We identified serine/threonine kinases and phosphorylated cytoskeletal signaling and synaptic vesicle proteins enriched with active Rac1. The phosphorylated sites in these proteins are at positions likely to have regulatory effects on synaptic vesicles. Consistent with this, we also report changes in the distribution and morphology of synaptic vesicles and in postsynaptic ultrastructure following presynaptic Rac1 inhibition. Overall, this study reveals a previously unrecognized presynaptic role of Rac1 signaling in cognitive processes and provides insights into its potential regulatory mechanisms.
PubMed: 38562715
DOI: 10.1101/2024.03.18.585488 -
Autophagy Oct 2023In neuronal synapses, autophagosome biogenesis is coupled with the activity-dependent synaptic vesicle cycle via ATG-9. How vesicles containing ATG-9 are sorted at the...
In neuronal synapses, autophagosome biogenesis is coupled with the activity-dependent synaptic vesicle cycle via ATG-9. How vesicles containing ATG-9 are sorted at the presynapse is unknown. We performed forward genetic screens at single synapses of neurons for mutants that disrupt ATG-9 presynaptic localization, and identified the long isoform of the active zone protein CLA-1 (Clarinet; CLA-1 L). We find that disrupting CLA-1 L results in abnormal accumulation of ATG-9-containing vesicles enriched with clathrin. The adaptor protein complexes and proteins at the periactive zone genetically interact with CLA-1 L in ATG-9 sorting. Moreover, the phenotype of the ATG-9 protein in mutants was not observed for integral synaptic vesicle proteins, suggesting distinct mechanisms that regulate sorting of ATG-9-containing vesicles and synaptic vesicles. Our findings reveal novel roles for active zone proteins in the sorting of ATG-9 and in presynaptic macroautophagy/autophagy.
Topics: Animals; Autophagy; Caenorhabditis elegans; Carrier Proteins; Presynaptic Terminals; Synapses; Synaptic Vesicles
PubMed: 37389488
DOI: 10.1080/15548627.2023.2229227 -
Nature Structural & Molecular Biology Jul 2023Synaptic vesicles are small membrane-enclosed organelles that store neurotransmitters at presynaptic terminals. The uniform morphology of synaptic vesicles is important...
Synaptic vesicles are small membrane-enclosed organelles that store neurotransmitters at presynaptic terminals. The uniform morphology of synaptic vesicles is important for brain function, because it enables the storage of well-defined amounts of neurotransmitters and thus reliable synaptic transmission. Here, we show that the synaptic vesicle membrane protein synaptogyrin cooperates with the lipid phosphatidylserine to remodel the synaptic vesicle membrane. Using NMR spectroscopy, we determine the high-resolution structure of synaptogyrin and identify specific binding sites for phosphatidylserine. We further show that phosphatidylserine binding changes the transmembrane structure of synaptogyrin and is critical for membrane bending and the formation of small vesicles. Cooperative binding of phosphatidylserine to both a cytoplasmic and intravesicular lysine-arginine cluster in synaptogyrin is required for the formation of small vesicles. Together with other synaptic vesicle proteins, synaptogyrin thus can sculpt the membrane of synaptic vesicles.
Topics: Synaptogyrins; Synaptic Vesicles; Phosphatidylserines; Nerve Tissue Proteins; Membrane Proteins; Synaptic Transmission
PubMed: 37217654
DOI: 10.1038/s41594-023-01004-9 -
Cell Reports Oct 2023The melanocortin-3 receptor (MC3R) is a negative regulator of the central melanocortin circuitry via presynaptic expression on agouti-related protein (AgRP) nerve...
The melanocortin-3 receptor (MC3R) is a negative regulator of the central melanocortin circuitry via presynaptic expression on agouti-related protein (AgRP) nerve terminals, from where it regulates GABA release onto secondary MC4R-expressing neurons. However, MC3R knockout (KO) mice also exhibit defective behavioral and neuroendocrine responses to fasting. Here, we demonstrate that MC3R KO mice exhibit defective activation of AgRP neurons in response to fasting, cold exposure, or ghrelin while exhibiting normal inhibition of AgRP neurons by sensory detection of food in the ad libitum-fed state. Using a conditional MC3R KO model, we show that the control of AgRP neuron activation by fasting and ghrelin requires the specific presence of MC3R within AgRP neurons. Thus, MC3R is a crucial player in the responsiveness of the AgRP soma to both hormonal and neuronal signals of energy need.
Topics: Mice; Animals; Agouti-Related Protein; Receptor, Melanocortin, Type 3; Ghrelin; Neurons; Mice, Knockout
PubMed: 37792535
DOI: 10.1016/j.celrep.2023.113188 -
Cell Death & Disease Apr 2024Abnormal intraneuronal accumulation of soluble and insoluble α-synuclein (α-Syn) is one of the main pathological hallmarks of synucleinopathies, such as Parkinson's...
Abnormal intraneuronal accumulation of soluble and insoluble α-synuclein (α-Syn) is one of the main pathological hallmarks of synucleinopathies, such as Parkinson's disease (PD). It has been well documented that the reversible liquid-liquid phase separation of α-Syn can modulate synaptic vesicle condensates at the presynaptic terminals. However, α-Syn can also form liquid-like droplets that may convert into amyloid-enriched hydrogels or fibrillar polymorphs under stressful conditions. To advance our understanding on the mechanisms underlying α-Syn phase transition, we employed a series of unbiased proteomic analyses and found that actin and actin regulators are part of the α-Syn interactome. We focused on Neural Wiskott-Aldrich syndrome protein (N-WASP) because of its association with a rare early-onset familial form of PD. In cultured cells, we demonstrate that N-WASP undergoes phase separation and can be recruited to synapsin 1 liquid-like droplets, whereas it is excluded from α-Syn/synapsin 1 condensates. Consistently, we provide evidence that wsp-1/WASL loss of function alters the number and dynamics of α-Syn inclusions in the nematode Caenorhabditis elegans. Together, our findings indicate that N-WASP expression may create permissive conditions that promote α-Syn condensates and their potentially deleterious conversion into toxic species.
Topics: alpha-Synuclein; Animals; Humans; Caenorhabditis elegans; Wiskott-Aldrich Syndrome Protein, Neuronal; Actins; Parkinson Disease; Synapsins; Caenorhabditis elegans Proteins
PubMed: 38693139
DOI: 10.1038/s41419-024-06686-7 -
Frontiers in Molecular Neuroscience 2023Amyotrophic Lateral Sclerosis (ALS) is characterised by a loss of motor neurons in the brain and spinal cord that is preceded by early-stage changes in synapses that may...
Amyotrophic Lateral Sclerosis (ALS) is characterised by a loss of motor neurons in the brain and spinal cord that is preceded by early-stage changes in synapses that may be associated with TAR-DNA-Binding Protein 43 (TDP-43) pathology. Cellular inclusions of hyperphosphorylated TDP-43 (pTDP-43) are a key hallmark of neurodegenerative diseases such ALS. However, there has been little characterisation of the synaptic expression of TDP-43 inside subpopulations of spinal cord synapses. This study utilises a range of high-resolution and super-resolution microscopy techniques with immunolabelling, as well as an aptamer-based TDP-43 labelling strategy visualised with single-molecule localisation microscopy, to characterise and quantify the presence of pTDP-43 in populations of excitatory synapses near where motor neurons reside in the lateral ventral horn of the mouse lumbar spinal cord. We observe that TDP-43 is expressed in approximately half of spinal cord synapses as nanoscale clusters. Synaptic TDP-43 clusters are found most abundantly at synapses associated with VGLUT1-positive presynaptic terminals, compared to VGLUT2-associated synapses. Our nanoscopy techniques showed no difference in the subsynaptic expression of pTDP-43 in the ALS mouse model, SOD1, compared to healthy controls, despite prominent structural deficits in VGLUT1-associated synapses in SOD1 mice. This research characterises the basic synaptic expression of TDP-43 with nanoscale precision and provides a framework with which to investigate the potential relationship between TDP-43 pathology and synaptic pathology in neurodegenerative diseases.
PubMed: 37671010
DOI: 10.3389/fnmol.2023.1027898 -
The Journal of Neuroscience : the... Jul 2023The rod photoreceptor synapse is the first synapse of dim-light vision and one of the most complex in the mammalian CNS. The components of its unique structure, a...
The rod photoreceptor synapse is the first synapse of dim-light vision and one of the most complex in the mammalian CNS. The components of its unique structure, a presynaptic ribbon and a single synaptic invagination enclosing several postsynaptic processes, have been identified, but disagreements about their organization remain. Here, we have used EM tomography to generate high-resolution images of 3-D volumes of the rod synapse from the female domestic cat. We have resolved the synaptic ribbon as a single structure, with a single arciform density, indicating the presence of one long site of transmitter release. The organization of the postsynaptic processes, which has been difficult to resolve with past methods, appears as a tetrad arrangement of two horizontal cell and two rod bipolar cell processes. Retinal detachment severely disrupts this organization. After 7 d, EM tomography reveals withdrawal of rod bipolar dendrites from most spherules; fragmentation of synaptic ribbons, which lose their tight association with the presynaptic membrane; and loss of the highly branched telodendria of the horizontal cell axon terminals. After detachment, the hilus, the opening through which postsynaptic processes enter the invagination, enlarges, exposing the normally sequestered environment within the invagination to the extracellular space of the outer plexiform layer. Our use of EM tomography provides the most accurate description to date of the complex rod synapse and details changes it undergoes during outer segment degeneration. These changes would be expected to disrupt the flow of information in the rod pathway. Ribbon-type synapses transmit the first electrical signals of vision and hearing. Despite their crucial role in sensory physiology, the three-dimensional ultrastructure of these synapses, especially the complex organization of the rod photoreceptor synapse, is not well understood. We used EM tomography to obtain 3-D imaging at nanoscale resolution to help resolve the organization of rod synapses in normal and detached retinas. This approach has enabled us to show that in the normal retina a single ribbon and arciform density oppose a tetrad of postsynaptic processes. In addition, it enabled us to provide a 3-D perspective of the ultrastructural changes that occur in response to retinal detachment.
Topics: Female; Animals; Cats; Retinal Detachment; Microscopy, Electron; Synapses; Retina; Retinal Bipolar Cells; Retinal Rod Photoreceptor Cells; Mammals
PubMed: 37414561
DOI: 10.1523/JNEUROSCI.2267-22.2023 -
Current Issues in Molecular Biology Oct 2023ATP, being a well-known universal high-energy compound, plays an important role as a signaling molecule and together with its metabolite adenosine they both attenuate...
ATP, being a well-known universal high-energy compound, plays an important role as a signaling molecule and together with its metabolite adenosine they both attenuate the release of acetylcholine in the neuro-muscular synapse acting through membrane P2 and P1 receptors, respectively. In this work, using a mechanomyographic method, we analyzed the presynaptic mechanisms by which ATP and adenosine can modulate the transduction in the rat and . N-ethylmaleimide, a G-protein antagonist, prevents the modulating effects of both ATP and adenosine. The action of ATP is abolished by chelerythrin, a specific phospholipase C inhibitor, while the inhibitory effect of adenosine is slightly increased by Rp-cAMPS, an inhibitor of protein kinase A, and by nitrendipine, a blocker of L-type Ca channels. The addition of DPCPX, an A receptor antagonist, fully prevents the inhibitory action of adenosine in both muscles. Our data indicate that the inhibitory action of ATP involves metabotropic P2Y receptors and is mediated by phospholipase C dependent processes in rat motor neuron terminals. We suggest that the presynaptic effect of adenosine consists of negative and positive actions. The negative action occurs by stimulation of adenosine A receptors while the positive action is associated with the stimulation of adenosine A receptors, activation of protein kinase A and opening of L-type calcium channels. The combined mechanism of the modulating action of ATP and adenosine provides fine tuning of the synapse to fast changing conditions in the skeletal muscles.
PubMed: 37886978
DOI: 10.3390/cimb45100535