The Membrane Interactions of Synuclein: Physiology and Pathology

2021 ◽  
Vol 16 (1) ◽  
pp. 465-485
Author(s):  
Gautam Runwal ◽  
Robert H. Edwards
Keyword(s):  
Human Genetics ◽  
Normal Function ◽  
Fusion Pore ◽  
Causative Role ◽  
Lewy Pathology ◽  
Synaptic Vesicle Exocytosis ◽  
Vesicle Exocytosis ◽  
Presynaptic Boutons ◽  
Specific Proteins

Specific proteins accumulate in neurodegenerative disease, and human genetics has indicated a causative role for many. In most cases, however, the mechanisms remain poorly understood. Degeneration is thought to involve a gain of abnormal function, although we do not know the normal function of many proteins implicated. The protein α-synuclein accumulates in the Lewy pathology of Parkinson's disease and related disorders, and mutations in α-synuclein cause degeneration, but we have not known its normal function or how it triggers disease. α-Synuclein localizes to presynaptic boutons and interacts with membranes in vitro. Overexpression slows synaptic vesicle exocytosis, and recent data suggest a normal role for the endogenous synucleins in dilation of the exocytic fusion pore. Disrupted membranes also appear surprisingly prominent in Lewy pathology. Synuclein thus interacts with membranes under both physiological and pathological conditions, suggesting that the normal function of synuclein may illuminate its role in degeneration.

scholarly journals Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

2016 ◽  
Vol 113 (29) ◽  
pp. 8314-8319 ◽  
Author(s):  
Tae-Sun Lee ◽  
Joo-Young Lee ◽  
Jae Won Kyung ◽  
Yoosoo Yang ◽  
Seung Ju Park ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Neurotransmitter Release ◽  
Hippocampal Neurons ◽  
Vesicle Fusion ◽  
Synaptic Membrane ◽  
Synaptic Vesicle Exocytosis ◽  
Dependent Inhibition ◽  
Vesicle Exocytosis ◽  
Inositol Pyrophosphates

Inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate (5-IP7) are highly energetic inositol metabolites containing phosphoanhydride bonds. Although inositol pyrophosphates are known to regulate various biological events, including growth, survival, and metabolism, the molecular sites of 5-IP7 action in vesicle trafficking have remained largely elusive. We report here that elevated 5-IP7 levels, caused by overexpression of inositol hexakisphosphate (IP6) kinase 1 (IP6K1), suppressed depolarization-induced neurotransmitter release from PC12 cells. Conversely, IP6K1 depletion decreased intracellular 5-IP7 concentrations, leading to increased neurotransmitter release. Consistently, knockdown of IP6K1 in cultured hippocampal neurons augmented action potential-driven synaptic vesicle exocytosis at synapses. Using a FRET-based in vitro vesicle fusion assay, we found that 5-IP7, but not 1-IP7, exhibited significantly higher inhibitory activity toward synaptic vesicle exocytosis than IP6. Synaptotagmin 1 (Syt1), a Ca2+ sensor essential for synaptic membrane fusion, was identified as a molecular target of 5-IP7. Notably, 5-IP7 showed a 45-fold higher binding affinity for Syt1 compared with IP6. In addition, 5-IP7–dependent inhibition of synaptic vesicle fusion was abolished by increasing Ca2+ levels. Thus, 5-IP7 appears to act through Syt1 binding to interfere with the fusogenic activity of Ca2+. These findings reveal a role of 5-IP7 as a potent inhibitor of Syt1 in controlling the synaptic exocytotic pathway and expand our understanding of the signaling mechanisms of inositol pyrophosphates.

Synapsin I is expressed in epithelial cells: localization to a unique trans-Golgi compartment

2001 ◽  
Vol 114 (20) ◽  
pp. 3695-3704 ◽  
Author(s):  
Rodrigo Bustos ◽  
E. Robert Kolen ◽  
Lelita Braiterman ◽  
Anthony J. Baines ◽  
Fred S. Gorelick ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Limited Proteolysis ◽  
Neuronal Cell ◽  
Synapsin I ◽  
Synaptic Vesicle Exocytosis ◽  
Golgi Compartment ◽  
Neuronal Cell Lines ◽  
Vesicle Exocytosis ◽  
Golgi Network

Synapsin I is abundant in neural tissues. Its phosphorylation is thought to regulate synaptic vesicle exocytosis in the pre-synaptic terminal by mediating vesicle tethering to the cytoskeleton. Using anti-synapsin antibodies, we detected an 85 kDa protein in liver cells and identified it as synapsin I. Like brain synapsin I, non-neuronal synapsin I is phosphorylated in vitro by protein kinase A and yields identical 32P-peptide maps after limited proteolysis. We also detected synapsin I mRNA in liver by northern blot analysis. These results indicate that the expression of synapsin I is more widespread than previously thought. Immunofluorescence analysis of several non-neuronal cell lines localizes synapsin I to a vesicular compartment adjacent to trans-elements of the Golgi complex, which is also labeled with antibodies against myosin II; no sub-plasma membrane synapsin I is evident. We conclude that synapsin I is present in epithelial cells and is associated with a trans-Golgi network-derived compartment; this localization suggests that it plays a role in modulating post-TGN trafficking pathways.

The Bovine Lens as a Model for Osmotic Cataract

1983 ◽  
Vol 11 (1) ◽  
pp. 5-13
Author(s):  
Julia M. Marcantonio
Keyword(s):  
Amino Acid ◽  
Defined Medium ◽  
Normal Function ◽  
In Vitro Testing ◽  
Ionic Balance ◽  
Acid Transport ◽  
Rapid Reduction ◽  
Membrane Function ◽  
Specific Proteins

Summary Bovine lenses, obtained from a commercial slaughterhouse, have been cultured successfully in a completely defined medium, for periods of up to two weeks. In control lenses, transparency is maintained, ionic balance and hydration are normal, and the amino acid L-tyrosine is in a steady state. Synthesis of the lens specific proteins continues throughout the culture period and there is no evidence of crystallin breakdown. Cultured lenses have been subjected to insult by various substances known to affect membrane function. In each case, ionic balance was disturbed, hydration was increased and there was gradual opacification of the lens. In addition, in the presence of ouabain, amino acid transport was decreased after a delay, while there was a very rapid reduction in protein synthesis. The cultured lens seems to be a very sensitive system which can be used as a model for investigations of normal function and for in vitro testing.

scholarly journals Probing synaptic vesicle fusion by altering mechanical properties of the neuronal surface membrane

2008 ◽  
Vol 105 (46) ◽  
pp. 18018-18022 ◽  
Author(s):  
Yongling Zhu ◽  
Charles F. Stevens
Keyword(s):  
Mechanical Properties ◽  
Synaptic Vesicle ◽  
Surface Membrane ◽  
Fusion Pore ◽  
Neuronal Membrane ◽  
Mechanical Process ◽  
Synaptic Vesicle Exocytosis ◽  
Fusion Probability ◽  
Vesicle Exocytosis ◽  
Synaptic Vesicle Fusion

Because synaptic vesicle exocytosis is a nano-mechanical process, it should be influenced by the mechanical properties of the cell membrane to which the vesicle fuses. By dissolving surfactants at various concentrations in the neuronal membrane, we have perturbed mechanical properties of the membrane and have found that dissolved surfactants lower the probability that a synaptic vesicle will open its fusion pore when the fusion machinery of the vesicle is activated by binding calcium. By using standard theories from the physics and chemistry of surfaces, we can account for this decrease in fusion probability and can infer that a vesicle, when activated, opens its fusion pore ≈3 times out of 4 and that the area of the fusion pore is ≈4 nm2.

scholarly journals Complexin-I-deficient sperm are subfertile due to a defect in zona pellucida penetration

Reproduction ◽  
2008 ◽  
Vol 136 (3) ◽  
pp. 323-334 ◽  
Author(s):  
Longmei Zhao ◽  
Kerstin Reim ◽  
David J Miller
Keyword(s):  
Zona Pellucida ◽  
Semen Analysis ◽  
Fertilization Rate ◽  
Computer Assisted ◽  
Cell Fractionation ◽  
Synaptic Vesicle Exocytosis ◽  
Protein Receptor ◽  
Vesicle Exocytosis ◽  
Deficient Mice

Upon adhesion to the zona pellucida, sperm undergo regulated exocytosis of the acrosome. Although it is necessary for sperm to penetrate the zona pellucida and fertilize an egg, the acrosomal membrane fusion process is poorly understood. Complexins I and II are small, cytosolic proteins that bind to a complex of proteins termed the solubleN-ethylmaleimide-sensitive factor attachment protein receptor complex to regulate synaptic vesicle exocytosis. Complexin-II-deficient mice are fertile but the fertility of sperm from complexin-I-deficient male mice is unclear because the mice have ataxia and cannot mate. Here, we show that the genes encoding complexins I and II are expressed in primary spermatocytes and spermatids. Complexin proteins were found in/near the developing acrosome in spermatids and in or around the acrosome of mature sperm. Cell fractionation demonstrated that complexins I and II were predominantly found in the cytosolic fraction. Furthermore, sperm from complexin-I-deficient mice had normal morphology, number, and only small differences in motility, as assessed by computer-assisted semen analysis. Complexin-I-deficient sperm capacitated normally and bound to the zona pellucida. But when sperm from complexin-I-deficient mice were inseminated into females, a defect in fertility was observed, in concordance with previous data showing thatin vitrofertilization rate was also reduced. If the zona pellucida was removed prior toin vitrofertilization, fertility was normal, demonstrating that zona pellucida penetration was defective, a step requiring acrosomal exocytosis. Therefore, complexin-I-deficient sperm are subfertile due to faulty zona pellucida penetration.

Uncertainties Associated with Assessing the Risk of an Endocrine Active Substance in the Canadian Environment

2001 ◽  
Vol 36 (2) ◽  
pp. 319-330 ◽  
Author(s):  
Mark Servos ◽  
Don Bennie ◽  
Kent Burnison ◽  
Philippa Cureton ◽  
Nicol Davidson ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Endocrine Disruption ◽  
Endocrine System ◽  
Problem Formulation ◽  
Normal Function ◽  
Weight Of Evidence ◽  
Biological Responses ◽  
Low Concentrations ◽  
Multigenerational Effects

Abstract A number of biological responses and multigenerational effects, mediated through the disruption of endocrine systems, have been observed in biota exposed to relatively low concentrations of environmental contaminants. These types of responses need to be considered within a weight of evidence approach in our risk assessment and risk management frameworks. However, including endocrine responses in an environmental risk assessment introduces a number of uncertainties that must be considered. A risk assessment of nonylphenol and nonylphenol polyethoxylates (NP/NPE) is used as a case study to demonstrate the sources and magnitude of some of the uncertainties associated with using endocrine disruption as an assessment endpoint. Even with this relatively well studied group of substances, there are substantial knowledge gaps which contribute to the overall uncertainties, limiting the interpretation within the risk assessment. The uncertainty of extrapolating from in vitro or biochemical responses to higher levels of organization or across species is not well understood. The endocrine system is very complex and chemicals can interact or interfere with the normal function of endocrine systems in a number of ways (e.g., receptors, hormones) which may or may not result in an adverse responses in the whole organism. Using endocrine responses can lead to different conclusions than traditional endpoints due to a variety of factors, such as differences in relative potencies of chemicals for specific endpoints (e.g., receptor binding versus chronic toxicity). The uncertainties can also be considerably larger and the desirability of using endocrine endpoints should be carefully evaluated. Endocrine disruption is a mode of action and not a functional endpoint and this needs to be considered carefully in the problem formulation stage and the interpretation of the weight of evidence.

iTSP-PseAAC: Identify Tumor Suppressor Proteins by Using Fully Connected Neural Network and PseAAC

2021 ◽  
Vol 15 ◽  
Author(s):  
Muhammad Awais ◽  
Waqar Hussain ◽  
Nouman Rasool ◽  
Yaser Daanial Khan
Keyword(s):  
Tumor Suppressor ◽  
Cross Validation ◽  
Control Cell ◽  
Normal Function ◽  
In Vivo Studies ◽  
Tumor Suppressor Proteins ◽  
Proposed Model ◽  
Self Consistency

Background: The uncontrolled growth due to accumulation of genetic and epigenetic changes as a result of loss or reduction in the normal function of Tumor Suppressor Genes (TSGs) and Pro-oncogenes is known as cancer. TSGs control cell division and growth by repairing of DNA mistakes during replication and restrict the unwanted proliferation of a cell or activities, those are the part of tumor production. Objectives: This study aims to propose a novel, accurate, user-friendly model to predict tumor suppressor proteins, which would be freely available to experimental molecular biologists to assist them using in vitro and in vivo studies. Methods: The predictor model has used the input feature vector (IFV) calculated from the physicochemical properties of proteins based on FCNN to compute the accuracy, sensitivity, specificity, and MCC. The proposed model was validated against different exhaustive validation techniques i.e. self-consistency and cross-validation. Results: Using self-consistency, the accuracy is 99%, for cross-validation and independent testing has 99.80% and 100% accuracy respectively. The overall accuracy of the proposed model is 99%, sensitivity value 98% and specificity 99% and F1-score was 0.99. Conclusion: It concludes, the proposed model for prediction of the tumor suppressor proteins can predict the tumor suppressor proteins efficiently, but it still has space for improvements in computational ways as the protein sequences may rapidly increase, day by day.

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