scholarly journals Effects of Excess Brain-Derived Human α-Synuclein on Synaptic Vesicle Trafficking

2021 ◽  
Vol 15 ◽  
Author(s):  
Cristina Román-Vendrell ◽  
Audrey T. Medeiros ◽  
John B. Sanderson ◽  
Haiyang Jiang ◽  
Tim Bartels ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Molecular Species ◽  
Vesicle Trafficking ◽  
Lewy Bodies ◽  
Minor Component ◽  
Synaptic Function ◽  
Normal Human Subject ◽  
Trafficking Defects ◽  
Synapse Model ◽  
The Brain

α-Synuclein is a presynaptic protein that regulates synaptic vesicle trafficking under physiological conditions. However, in several neurodegenerative diseases, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, α-synuclein accumulates throughout the neuron, including at synapses, leading to altered synaptic function, neurotoxicity, and motor, cognitive, and autonomic dysfunction. Neurons typically contain both monomeric and multimeric forms of α-synuclein, and it is generally accepted that disrupting the balance between them promotes aggregation and neurotoxicity. However, it remains unclear how distinct molecular species of α-synuclein affect synapses where α-synuclein is normally expressed. Using the lamprey reticulospinal synapse model, we previously showed that acute introduction of excess recombinant monomeric or dimeric α-synuclein impaired distinct stages of clathrin-mediated synaptic vesicle endocytosis, leading to a loss of synaptic vesicles. Here, we expand this knowledge by investigating the effects of native, physiological α-synuclein isolated from the brain of a neuropathologically normal human subject, which comprised predominantly helically folded multimeric α-synuclein with a minor component of monomeric α-synuclein. After acute introduction of excess brain-derived human α-synuclein, there was a moderate reduction in the synaptic vesicle cluster and an increase in the number of large, atypical vesicles called “cisternae.” In addition, brain-derived α-synuclein increased synaptic vesicle and cisternae sizes and induced atypical fusion/fission events at the active zone. In contrast to monomeric or dimeric α-synuclein, the brain-derived multimeric α-synuclein did not appear to alter clathrin-mediated synaptic vesicle endocytosis. Taken together, these data suggest that excess brain-derived human α-synuclein impairs intracellular vesicle trafficking and further corroborate the idea that different molecular species of α-synuclein produce distinct trafficking defects at synapses. These findings provide insights into the mechanisms by which excess α-synuclein contributes to synaptic deficits and disease phenotypes.

scholarly journals Hsc70 Ameliorates the Vesicle Recycling Defects Caused by Excess α-Synuclein at Synapses

2019 ◽  
Author(s):  
Susan M. L. Banks ◽  
Audrey T. Medeiros ◽  
Molly McQuillan ◽  
David J. Busch ◽  
Ana Sofia Ibarraran-Viniegra ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Cognitive Deficits ◽  
Vesicle Trafficking ◽  
Lewy Bodies ◽  
Synaptic Vesicle Recycling ◽  
Vesicle Recycling ◽  
Chaperone Protein ◽  
Trafficking Defects ◽  
Underlying Mechanisms

ABSTRACTα-Synuclein overexpression and aggregation are linked to Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and several other neurodegenerative disorders. In addition to effects in the cell body, α-synuclein accumulation occurs at presynapses where the protein is normally localized. While it is generally agreed that excess α-synuclein impairs synaptic vesicle trafficking, the underlying mechanisms are unknown. We show here that acute introduction of excess human α-synuclein at a classic vertebrate synapse, the lamprey reticulospinal synapse, selectively impaired the uncoating of clathrin-coated vesicles (CCVs) during synaptic vesicle recycling, leading to a severe depletion of synaptic vesicles. Furthermore, human α-synuclein and lamprey γ-synuclein both interact in vitro with Hsc70, the chaperone protein that uncoats CCVs at synapses. After introducing excess α-synuclein to lamprey axons, Hsc70 availability was reduced at the synapses, suggesting Hsc70 sequestration as a possible mechanism underlying the synaptic vesicle trafficking defects. In support of this hypothesis, increasing the levels of exogenous Hsc70 together with α-synuclein ameliorated the CCV uncoating and vesicle recycling defects. These experiments identify a reduction in Hsc70 availability at synapses, and consequently its function, as the mechanism by which α-synuclein induces synaptic vesicle recycling defects. To our knowledge, this is the first report of a viable chaperone-based strategy for reversing the toxic impacts of excess α-synuclein at synapses, which may be of value for ameliorating synaptic defects in PD and other synuclein-linked diseases.SIGNIFICANCE STATEMENTSynaptic defects caused by α-synuclein overexpression are linked to cognitive deficits in PD and other diseases. However, the mechanisms by which excess α-synuclein impairs synaptic vesicle trafficking are unknown. Data presented here demonstrate that acute introduction of excess α-synuclein at a classical vertebrate synapse selectively inhibits CCV uncoating, leading to impaired vesicle recycling. Furthermore, increasing α-synuclein reduced synaptic levels of Hsc70, the clathrin uncoating ATPase. Subsequently increasing Hsc70 restored CCV uncoating and improved vesicle recycling. This study identifies a novel molecular mechanism underlying the α-synuclein-induced synaptic defects and presents one viable strategy for reversing them.

Effects of High BMI on Synaptic Function and Metabolic Connectivity in the Brain—Evidence of Gender Difference

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 363-OR ◽  
Author(s):  
ARIANNA SALA ◽  
MAURA MALPETTI ◽  
ANNA FERRULLI ◽  
LUIGI GIANOLLI ◽  
LIVIO LUZI ◽  
...  
Keyword(s):  
Gender Difference ◽  
Synaptic Function ◽  
Metabolic Connectivity ◽  
The Brain ◽  
High Bmi

scholarly journals Altered network properties in C9ORF72 repeat expansion cortical neurons are due to synaptic dysfunction

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Emma M. Perkins ◽  
Karen Burr ◽  
Poulomi Banerjee ◽  
Arpan R. Mehta ◽  
Owen Dando ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Synaptic Vesicle ◽  
Cortical Neurons ◽  
Electrode Array ◽  
Repeat Expansion ◽  
Cortical Network ◽  
Synaptic Function ◽  
Network Activity ◽  
Cortical Function ◽  
Network Function

Abstract Background Physiological disturbances in cortical network excitability and plasticity are established and widespread in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those harbouring the C9ORF72 repeat expansion (C9ORF72RE) mutation – the most common genetic impairment causal to ALS and FTD. Noting that perturbations in cortical function are evidenced pre-symptomatically, and that the cortex is associated with widespread pathology, cortical dysfunction is thought to be an early driver of neurodegenerative disease progression. However, our understanding of how altered network function manifests at the cellular and molecular level is not clear. Methods To address this we have generated cortical neurons from patient-derived iPSCs harbouring C9ORF72RE mutations, as well as from their isogenic expansion-corrected controls. We have established a model of network activity in these neurons using multi-electrode array electrophysiology. We have then mechanistically examined the physiological processes underpinning network dysfunction using a combination of patch-clamp electrophysiology, immunocytochemistry, pharmacology and transcriptomic profiling. Results We find that C9ORF72RE causes elevated network burst activity, associated with enhanced synaptic input, yet lower burst duration, attributable to impaired pre-synaptic vesicle dynamics. We also show that the C9ORF72RE is associated with impaired synaptic plasticity. Moreover, RNA-seq analysis revealed dysregulated molecular pathways impacting on synaptic function. All molecular, cellular and network deficits are rescued by CRISPR/Cas9 correction of C9ORF72RE. Our study provides a mechanistic view of the early dysregulated processes that underpin cortical network dysfunction in ALS-FTD. Conclusion These findings suggest synaptic pathophysiology is widespread in ALS-FTD and has an early and fundamental role in driving altered network function that is thought to contribute to neurodegenerative processes in these patients. The overall importance is the identification of previously unidentified defects in pre and postsynaptic compartments affecting synaptic plasticity, synaptic vesicle stores, and network propagation, which directly impact upon cortical function.

scholarly journals Importance of Nanoparticles for the Delivery of Antiparkinsonian Drugs

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 508
Author(s):  
Sara Silva ◽  
António J. Almeida ◽  
Nuno Vale
Keyword(s):  
Side Effects ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Pharmacokinetic Profile ◽  
The Elderly ◽  
Motor Symptoms ◽  
Administration Routes ◽  
Pharmaceutical Therapy ◽  
Drug Pharmacokinetic ◽  
The Brain

Parkinson’s disease (PD) affects around ten million people worldwide and is considered the second most prevalent neurodegenerative disease after Alzheimer’s disease. In addition, there is a higher risk incidence in the elderly population. The main PD hallmarks include the loss of dopaminergic neurons and the development of Lewy bodies. Unfortunately, motor symptoms only start to appear when around 50–70% of dopaminergic neurons have already been lost. This particularly poses a huge challenge for early diagnosis and therapeutic effectiveness. Actually, pharmaceutical therapy is able to relief motor symptoms, but as the disease progresses motor complications and severe side-effects start to appear. In this review, we explore the research conducted so far in order to repurpose drugs for PD with the use of nanodelivery systems, alternative administration routes, and nanotheranostics. Overall, studies have demonstrated great potential for these nanosystems to target the brain, improve drug pharmacokinetic profile, and decrease side-effects.

scholarly journals Species pattern of phosphatidylinositol from lung surfactant and a comparison of the species pattern of phosphatidylinositol and phosphatidylglycerol synthesized de novo in lung microsomal fractions

1988 ◽  
Vol 254 (1) ◽  
pp. 67-71 ◽  
Author(s):  
B Rüstow ◽  
Y Nakagawa ◽  
H Rabe ◽  
K Waku ◽  
D Kunze
Keyword(s):  
Lung Function ◽  
Molecular Species ◽  
De Novo ◽  
Lung Surfactant ◽  
Minor Component ◽  
Main Species ◽  
Surfactant Phospholipids ◽  
Species Pattern ◽  
A Minor

1. Phosphatidylinositol (PI) is a minor component of lung surfactant which may be able to replace the functionally important phosphatidylglycerol (PG) [Beppu, Clements & Goerke (1983) J. Appl. Physiol. 55, 496-502] without disturbing lung function. The dipalmitoyl species is one of the main species for both PI (14.4%) and PG (16.9%). Besides the C16:0--C16:0 species, the C16:0--C18:0, C16:0--C18:1, C16:0--C18:2 and C18:0--C18:1 species showed comparable proportions in the PG and PI fractions. These similarities of the species patterns and the acidic character of both phospholipids could explain why surfactant PG may be replaced by PI. 2. PI and PG were radiolabelled by incubation of microsomal fractions with [14C]glycerol 3-phosphate (Gro3P). For 11 out of 14 molecular species of PI and PG we measured comparable proportions of radioactivity. The radioactivity of these 11 species accounted together for more than 80% of the total. The addition of inositol to the incubation system decreased the incorporation in vitro of Gro3P into PG and CDP-DG (diacylglycerol) of lung microsomes (microsomal fractions), but did not change the distribution of radioactivity among the molecular species of PG. These results supported the idea that both acidic surfactant phospholipids may be synthesized de novo from a common CDP-DG pool in lung microsomes.

scholarly journals Calcium-Dependent Synaptic Vesicle Trafficking Underlies Indefatigable Release at the Hair Cell Afferent Fiber Synapse

Neuron ◽  
2011 ◽  
Vol 70 (2) ◽  
pp. 326-338 ◽  
Author(s):  
Michael E. Schnee ◽  
Joseph Santos-Sacchi ◽  
Manuel Castellano-Muñoz ◽  
Jee-Hyun Kong ◽  
Anthony J. Ricci
Keyword(s):  
Hair Cell ◽  
Synaptic Vesicle ◽  
Vesicle Trafficking ◽  
Afferent Fiber ◽  
Calcium Dependent

scholarly journals Anti-aggregation Effects of Phenolic Compounds on α-synuclein

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2444
Author(s):  
Kenjiro Ono ◽  
Mayumi Tsuji ◽  
Tritia R. Yamasaki ◽  
Giulio M. Pasinetti
Keyword(s):  
Phenolic Compounds ◽  
Gut Microbiota ◽  
Lewy Bodies ◽  
Hydroxybenzoic Acid ◽  
Dietary Polyphenols ◽  
Pathologic Features ◽  
Hydroxyphenylacetic Acid ◽  
A Cell ◽  
The Brain

The aggregation and deposition of α-synuclein (αS) are major pathologic features of Parkinson’s disease, dementia with Lewy bodies, and other α-synucleinopathies. The propagation of αS pathology in the brain plays a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that attenuate αS aggregation and propagation. Based on cumulative evidence that αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies, we and other groups reported that phenolic compounds inhibit αS aggregation including oligomerization, thereby ameliorating αS oligomer-induced cellular and synaptic toxicities. Heterogeneity in gut microbiota may influence the efficacy of dietary polyphenol metabolism. Our recent studies on the brain-penetrating polyphenolic acids 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-hydroxyphenylacetic acid (3-HPPA), which are derived from gut microbiota-based metabolism of dietary polyphenols, demonstrated an in vitro ability to inhibit αS oligomerization and mediate aggregated αS-induced neurotoxicity. Additionally, 3-HPPA, 3,4-diHBA, 3-HBA, and 4-hydroxybenzoic acid significantly attenuated intracellular αS seeding aggregation in a cell-based system. This review focuses on recent research developments regarding neuroprotective properties, especially anti-αS aggregation effects, of phenolic compounds and their metabolites by the gut microbiome, including our findings in the pathogenesis of α-synucleinopathies.

scholarly journals Study on the Dynamic Changes in Synaptic Vesicle-Associated Protein and Axonal Transport Protein Combined with LPS Neuroinflammation Model

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Rui Zhang ◽  
Ming Zhao ◽  
Hai-jie Ji ◽  
Yu-he Yuan ◽  
Nai-hong Chen
Keyword(s):  
Neurodegenerative Disease ◽  
Synaptic Vesicle ◽  
Axonal Transport ◽  
Molecular Mechanism ◽  
Transport Protein ◽  
Microglia Activation ◽  
Time Dependent ◽  
Inflammatory Factors ◽  
Dynamic Changes ◽  
The Brain

Microglia activation is the major component of inflammation that constitutes the characteristic of neurodegenerative disease. A large amount of researches have demonstrated that inflammation involved in the pathogenesis of PD process activated microglia acting on the neurons through the release of a variety of inflammatory factors. However, the molecular mechanism underlying how it does work on neurons is still unclear. Here, we show that intracerebral injections of LPS induced Parkinson’s disease pathology in C57BL/6J mice. Furthermore, study on the dynamic changes in Synaptic vesicle-associated protein and axonal transport Protein in this process. The results indicated that after administration of LPS in the brain, the inflammatory levels of TNF-α and IL-1β both are elevated, and have a time-dependent.

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