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Neurotoxicity Research Jun 2021Methamphetamine (METH), a highly addictive psychostimulant, is the second most widely used illicit drug. METH produces damage dopamine neurons and apoptosis via multiple... (Review)
Review
Methamphetamine (METH), a highly addictive psychostimulant, is the second most widely used illicit drug. METH produces damage dopamine neurons and apoptosis via multiple inter-regulating mechanisms, including dopamine overload, hyperthermia, oxidative stress, mitochondria dysfunction, endoplasmic reticulum stress, protein degradation system dysfunction, and neuroinflammation. Increasing evidence suggests that chronic METH abuse is associated with neurodegenerative changes in the human brain and an increased risk of Parkinson's disease (PD). METH use and PD may share some common steps in causing neurotoxicity. Accumulation of α-synuclein, a presynaptic protein, is the pathological hallmark of PD. Intriguingly, α-synuclein upregulation and aggregation are also found in dopaminergic neurons in the substantia nigra in chronic METH users. This suggests α-synuclein may play a role in METH-induced neurotoxicity. The mechanism of α-synuclein cytotoxicity in PD has attracted considerable attention; however, how α-synuclein affects METH-induced neurotoxicity has not been reviewed. In this review, we summarize the relationship between METH use and PD, interdependent mechanisms that are involved in METH-induced neurotoxicity and the significance of α-synuclein upregulation in response to METH use. The identification of α-synuclein overexpression and aggregation as a contributor to METH-induced neurotoxicity may provide a novel therapeutic target for the treatment of the deleterious effect of this drug and drug addiction.
Topics: Animals; Central Nervous System Stimulants; Humans; Methamphetamine; Neurotoxicity Syndromes; alpha-Synuclein
PubMed: 33555547
DOI: 10.1007/s12640-021-00332-2 -
Cell Biochemistry and Biophysics Sep 2023α-Synucleinopathies are a group of neurodegenerative disorders characterized by alterations in α-synuclein (α-syn), a protein associated with membrane phospholipids,...
α-Synucleinopathies are a group of neurodegenerative disorders characterized by alterations in α-synuclein (α-syn), a protein associated with membrane phospholipids, whose precise function in normal cells is still unknown. These kinds of diseases are caused by multiple factors, but the regulation of the α-syn gene is believed to play a central role in the pathology of these disorders; therefore, the α-syn gene is one of the most studied genes. α-Synucleinopathies are complex disorders that derive from the interaction between genetic and environmental factors. Here, we offer an update on the landscape of the epigenetic regulation of α-syn gene expression that has been linked with α-synucleinopathies. We also delve into the reciprocal influence between epigenetic modifications and other factors related to these disorders, such as posttranslational modifications, microbiota participation, interactions with lipids, neuroinflammation and oxidative stress, to promote α-syn aggregation by acting on the transcription and/or translation of the α-syn gene.
Topics: Humans; Synucleinopathies; Epigenesis, Genetic; alpha-Synuclein
PubMed: 37526884
DOI: 10.1007/s12013-023-01154-z -
Essays in Biochemistry Dec 2022α-Synuclein (α-Syn) is a natively unstructured protein, which self-assembles into higher-order aggregates possessing serious pathophysiological implications. α-Syn... (Review)
Review
α-Synuclein (α-Syn) is a natively unstructured protein, which self-assembles into higher-order aggregates possessing serious pathophysiological implications. α-Syn aberrantly self-assembles into protein aggregates, which have been widely implicated in Parkinson's disease (PD) pathogenesis and other synucleinopathies. The self-assembly of α-Syn involves the structural conversion of soluble monomeric protein into oligomeric intermediates and eventually fibrillar aggregates of amyloids with cross-β-sheet rich conformation. These aggregated α-Syn species majorly constitute the intraneuronal inclusions, which is a hallmark of PD neuropathology. Self-assembly/aggregation of α-Syn is not a single-state conversion process as unfolded protein can access multiple conformational states through the formation of metastable, transient pre-fibrillar intermediate species. Recent studies have indicated that soluble oligomers are the potential neurotoxic species responsible for cell death in PD pathogenesis. The heterogeneous and transient nature of oligomers formed during the early stage of aggregation pathway limit their detailed study in understanding the structure-toxicity relationship. Moreover, the precise molecular events occurring in the early stage of α-Syn aggregation process majorly remain unsolved. Recently, liquid-liquid phase separation (LLPS) of α-Syn has been designated as an alternate nucleation mechanism, which occurs in the early lag phase of the aggregation pathway leading to the formation of dynamic supramolecular assemblies. The stronger self-association among the protein molecules triggers the irreversible liquid-to-solid transition of these supramolecular assemblies into the amyloid-like hydrogel, which may serve as a reservoir entrapping toxic oligomeric intermediates and fibrils. This review strives to provide insights into different modes of α-Syn self-assemblies including LLPS-mediated self-assembly and its recent advancements.
Topics: Humans; alpha-Synuclein; Protein Aggregates; Parkinson Disease; Amyloid; Intrinsically Disordered Proteins
PubMed: 36373662
DOI: 10.1042/EBC20220055 -
Brain, Behavior, and Immunity Jul 2021Alpha-synuclein (α-syn) which encoded by SNCA plays a critical role in the neurotransmission, vesicle dynamics, and neuroplasticity. Alteration to SNCA expression is...
Alpha-synuclein (α-syn) which encoded by SNCA plays a critical role in the neurotransmission, vesicle dynamics, and neuroplasticity. Alteration to SNCA expression is associated with major depressive disorder. However, the pathogenic mechanism of SNCA in depression remains unknown. Herein, we reported that SNCA was up-regulated in the peripheral blood of major depressive disorder (MDD) patients and the depressive mice. Chronic restraint stress (CRS) also up-regulated the SNCA expression in the hippocampus. Moreover, over-expression of SNCA in the hippocampus triggered spontaneous depressive-like behaviors under the non-stressed conditions in mice, and knockout of SNCA could reverse CRS-induced depressive-like behaviors. SNCA led to synapse loss and neuronal cell death in the hippocampus possibly via complement-mediated microglial engulfment and inflammation, and thus contributed to the pathogenesis of depressive disorder. Overall, hippocampal SNCA and complement system are involved in the pathogenesis of depressive disorder and it provides a new perspective for the occurrence of depressive disorder.
Topics: Animals; Depressive Disorder, Major; Hippocampus; Humans; Mice; Neuronal Plasticity; Synaptic Transmission; alpha-Synuclein
PubMed: 33775831
DOI: 10.1016/j.bbi.2021.03.020 -
Platelets Dec 2023Platelets play many roles in the vasculature ensuring proper hemostasis and maintaining integrity. These roles are facilitated, in part, by cargo molecules released from...
Platelets play many roles in the vasculature ensuring proper hemostasis and maintaining integrity. These roles are facilitated, in part, by cargo molecules released from platelet granules via oluble SF ttachment rotein eceptor (SNARE) mediated membrane fusion, which is controlled by several protein-protein interactions. Chaperones have been characterized for t-SNAREs (. Munc18b for Syntaxin-11), but none have been clearly identified for v-SNAREs. α-Synuclein has been proposed as a v-SNARE chaperone which may affect SNARE-complex assembly, fusion pore opening, and thus secretion. Despite its abundance and that it is the only isoform present, α-synuclein's role in platelet secretion is uncharacterized. In this study, immunofluorescence showed that α-synuclein was present on punctate structures that co-stained with markers for α-granules and lysosomes and in a cytoplasmic pool. We analyzed the phenotype of α-synuclein mice and their platelets. Platelets from knockout mice had a mild, agonist-dependent secretion defect but aggregation and spreading were unaffected. Consistently, thrombosis/hemostasis were unaffected in the tail-bleeding, FeCl carotid injury and jugular vein puncture models. None of the platelet secretory machinery examined, . the v-SNAREs, were affected by α-synuclein's loss. The results indicate that, despite its abundance, α-synuclein has only a limited role in platelet function and thrombosis.
Topics: Animals; Mice; alpha-Synuclein; Blood Platelets; Cytoplasmic Granules; Exocytosis; Mice, Knockout; Platelet Activation; Protein Isoforms; SNARE Proteins; Thrombosis
PubMed: 37927048
DOI: 10.1080/09537104.2023.2267147 -
Nature Communications Jul 2022Pathogenic α-synuclein (α-syn) is a prion-like protein that drives the pathogenesis of Lewy Body Dementia (LBD) and Parkinson's Disease (PD). To target pathogenic...
Pathogenic α-synuclein (α-syn) is a prion-like protein that drives the pathogenesis of Lewy Body Dementia (LBD) and Parkinson's Disease (PD). To target pathogenic α-syn preformed fibrils (PFF), here we designed extracellular disulfide bond-free synthetic nanobody libraries in yeast. Following selection, we identified a nanobody, PFFNB2, that can specifically recognize α-syn PFF over α-syn monomers. PFFNB2 cannot inhibit the aggregation of α-syn monomer, but can significantly dissociate α-syn fibrils. Furthermore, adeno-associated virus (AAV)-encoding EGFP fused to PFFNB2 (AAV-EGFP-PFFNB2) can inhibit PFF-induced α-syn serine 129 phosphorylation (pS129) in mouse primary cortical neurons, and prevent α-syn pathology spreading to the cortex in the transgenic mice expressing human wild type (WT) α-syn by intrastriatal-PFF injection. The pS129 immunoreactivity is negatively correlated with the expression of AAV-EGFP-PFFNB2. In conclusion, PFFNB2 holds a promise for mechanistic exploration and therapeutic development in α-syn-related pathogenesis.
Topics: Animals; Humans; Lewy Body Disease; Mice; Parkinson Disease; Prions; Synucleinopathies; alpha-Synuclein
PubMed: 35853942
DOI: 10.1038/s41467-022-31787-2 -
Handbook of Clinical Neurology 2022Alpha-synuclein (α-synuclein) is a small, acidic protein containing 140 amino acids, highly expressed in the brain and primarily localized in the presynaptic terminals.... (Review)
Review
Alpha-synuclein (α-synuclein) is a small, acidic protein containing 140 amino acids, highly expressed in the brain and primarily localized in the presynaptic terminals. It is found in high concentrations in Lewy Bodies, proteinaceous aggregates that constitute a typical histopathologic hallmark of Parkinson's disease. Altered environmental conditions, genetic mutations and post-translational changes can trigger abnormal aggregation processes with the increased frequency of oligomers, protofibrils, and fibrils formation that perturbs the neuronal homeostasis leading to cell death. Relevant to neuronal activity, a function of α-synuclein that has been extensively detailed is its regulatory actions in the trafficking of synaptic vesicles, including the processes of exocytosis, endocytosis and neurotransmitter release. Most recently, increasing attention has been paid to the possible role that α-synuclein plays at a postsynaptic level by interacting with selective subunits of the glutamate N-methyl-d-aspartate receptor, altering the corticostriatal plasticity of distinct neuronal populations.
Topics: Animals; Corpus Striatum; Disease Models, Animal; Humans; Lewy Bodies; Models, Animal; Parkinson Disease; alpha-Synuclein
PubMed: 35034731
DOI: 10.1016/B978-0-12-819410-2.00008-4 -
Chemistry and Physics of Lipids Mar 2021Parkinson's disease (PD) is the second most common neurodegenerative disease. Currently, PD has no treatment. The neuronal protein α-synuclein (αS) plays an important... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disease. Currently, PD has no treatment. The neuronal protein α-synuclein (αS) plays an important role in PD. However, the molecular mechanisms governing its physiological and pathological roles are not fully understood. It is becoming widely acknowledged that the biological roles of αS involve interactions with biological membranes. In these biological processes there is a fine-tuned interplay between lipids affecting the properties of αS and αS affecting lipid metabolism, αS binding to membranes, and membrane damage. In this review, the intricate interactions between αS and membranes will be reviewed and a discussion of the relationship between αS and neuronal membrane structural plasticity in health and disease will be made. It is proposed that in healthy neurons the conformational flexibilities of αS and the neuronal membranes are coupled to assist the physiological roles of αS. However, in circumstances where their conformational flexibilities are decreased or uncoupled, there is a shift toward cell toxicity. Strategies to modulate toxic αS-membrane interactions are potential approaches for the development of new therapies for PD. Future work using specific αS molecular species as well as membranes with specific physicochemical properties should widen our understanding of the intricate biological roles of αS which, in turn, would propel the development of new strategies for the treatment of PD.
Topics: Cell Membrane; Humans; Molecular Conformation; Neurodegenerative Diseases; Neurons; alpha-Synuclein
PubMed: 33434528
DOI: 10.1016/j.chemphyslip.2020.105034 -
Seminars in Cell & Developmental Biology Mar 2020α-synuclein and Tau are proteins prone to pathological misfolding and aggregation that are normally found in the presynaptic and axonal compartments of neurons.... (Review)
Review
α-synuclein and Tau are proteins prone to pathological misfolding and aggregation that are normally found in the presynaptic and axonal compartments of neurons. Misfolding initiates a homo-oligomerization and aggregation cascade culminating in cerebral accumulation of aggregated α-synuclein and Tau in insoluble protein inclusions in multiple neurodegenerative diseases. Traditionally, α-synuclein-containing Lewy bodies have been associated with Parkinson's disease and Tau-containing neurofibrillary tangles with Alzheimer's disease and various frontotemporal dementia syndromes. However, there is significant overlap and co-occurrence of α-synuclein and Tau pathologies in a spectrum of neurodegenerative diseases. Importantly, α-synuclein and Tau can interact in cells, and their pathological conformations are capable of templating further misfolding and aggregation of each other. They also share a number of protein interactors indicating that network perturbations may contribute to chronic proteotoxic stress and neuronal dysfunction in synucleinopathies and tauopathies, some of which share similarities in both neuropathological and clinical manifestations. In this review, we focus on the protein interactions of these two pathologically important proteins and consider a network biology perspective towards neurodegenerative diseases.
Topics: Animals; Humans; Neurodegenerative Diseases; alpha-Synuclein; tau Proteins
PubMed: 29738880
DOI: 10.1016/j.semcdb.2018.05.005 -
Journal of Neurochemistry Apr 2020Protein aggregation plays a central role in numerous neurodegenerative diseases. The key proteins in these diseases are of significant importance, but their...
Disentangling aggregation-prone proteins: a new method for isolating α-synuclein species: An Editorial Highlight for "A simple, versatile and robust centrifugation-based filtration protocol for the isolation and quantification of α-synuclein monomers, oligomers and fibrils: Towards improving...
Protein aggregation plays a central role in numerous neurodegenerative diseases. The key proteins in these diseases are of significant importance, but their investigation can be challenging due to unique properties of protein misfolding and oligomerization. Alpha-synuclein protein (α-Syn) is the predominant component of Lewy Bodies in Parkinson's disease (PD) and is a member of this class of proteins. Many α-Syn studies are limited by the inability to separate various monomeric, oligomeric, and fibrillar forms of the protein from heterogeneous mixtures. This Editorial Highlight summarizes the impact of a study published in the current issue of Journal of Neurochemistry, in which Lashuel and colleagues developed a simple, rapid centrifugation- and filter-based method for separating, isolating, and quantifying different forms of α-Syn. The researchers used electron microscopy, SDS-PAGE, circular dichroism, and protein assays to carefully validate the method and quantitate α-Syn yields and loss. The publication of this new method will not only aid in future studies of α-Syn, but will likely extend to other proteins that underlie a variety of neurodegenerative diseases.
Topics: Centrifugation; Filtration; Humans; Parkinson Disease; Protein Aggregation, Pathological; Reproducibility of Results; alpha-Synuclein
PubMed: 32037541
DOI: 10.1111/jnc.14973