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Cell Death & Disease Jul 2012The aggregation, deposition, and dysfunction of alpha-synuclein (aSyn) are common events in neurodegenerative disorders known as synucleinopathies. These include... (Review)
Review
The aggregation, deposition, and dysfunction of alpha-synuclein (aSyn) are common events in neurodegenerative disorders known as synucleinopathies. These include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. A growing body of knowledge on the biology of aSyn is emerging and enabling novel hypotheses to be tested. In particular, the hypothesis that aSyn is secreted from neurons, thus contributing to the spreading of pathology not only in the brain but also in other organs, is gaining momentum. Nevertheless, the precise mechanism(s) of secretion, as well as the consequences of extracellular aSyn species for neighboring cells are still unclear. Here, we review the current literature and integrate existing data in order to propose possible mechanisms of secretion, cell dysfunction, and death. Ultimately, the complete understanding of these processes might open novel avenues for the development of new therapeutic strategies.
Topics: Animals; Apoptosis; Humans; Parkinson Disease; Protein Folding; alpha-Synuclein
PubMed: 22825468
DOI: 10.1038/cddis.2012.94 -
Biomolecules May 2015Mutations and duplication/triplication of the alpha-synuclein (αSyn)-coding gene have been found to cause familial Parkinson's disease (PD), while genetic polymorphisms... (Review)
Review
Mutations and duplication/triplication of the alpha-synuclein (αSyn)-coding gene have been found to cause familial Parkinson's disease (PD), while genetic polymorphisms in the region controlling the expression level and stability of αSyn have been identified as risk factors for idiopathic PD, pointing to the importance of wild-type (wt) αSyn dosage in the disease. Evidence that αSyn is present in the cerebrospinal fluid and interstitial brain tissue and that healthy neuronal grafts transplanted into PD patients often degenerate suggests that extracellularly-released αSyn plays a role in triggering the neurodegenerative process. αSyn's role in neurotransmission has been shown in various cell culture models in which the protein was upregulated or deleted and in knock out and transgenic animal, with different results on αSyn's effect on synaptic vesicle pool size and mobilization, αSyn being proposed as a negative or positive regulator of neurotransmitter release. In this review, we discuss the effect of αSyn on pre- and post-synaptic compartments in terms of synaptic vesicle trafficking, calcium entry and channel activity, and we focus on the process of exocytosis and internalization of αSyn and on the spreading of αSyn-driven effects due to the presence of the protein in the extracellular milieu.
Topics: Animals; Exocytosis; Humans; Parkinson Disease; Synaptic Transmission; alpha-Synuclein
PubMed: 25985082
DOI: 10.3390/biom5020865 -
Biomolecules Jul 2015α-Synuclein inclusion bodies are a pathological hallmark of several neurodegenerative diseases, including Parkinson's disease, and contain aggregated α-synuclein and a... (Review)
Review
α-Synuclein inclusion bodies are a pathological hallmark of several neurodegenerative diseases, including Parkinson's disease, and contain aggregated α-synuclein and a variety of recruited factors, including protein chaperones, proteasome components, ubiquitin and the small ubiquitin-like modifier, SUMO-1. Cell culture and animal model studies suggest that misfolded, aggregated α-synuclein is actively translocated via the cytoskeletal system to a region of the cell where other factors that help to lessen the toxic effects can also be recruited. SUMO-1 covalently conjugates to various intracellular target proteins in a way analogous to ubiquitination to alter cellular distribution, function and metabolism and also plays an important role in a growing list of cellular pathways, including exosome secretion and apoptosis. Furthermore, SUMO-1 modified proteins have recently been linked to cell stress responses, such as oxidative stress response and heat shock response, with increased SUMOylation being neuroprotective in some cases. Several recent studies have linked SUMOylation to the ubiquitin-proteasome system, while other evidence implicates the lysosomal pathway. Other reports depict a direct mechanism whereby sumoylation reduced the aggregation tendency of α-synuclein, and reduced the toxicity. However, the precise role of SUMO-1 in neurodegeneration remains unclear. In this review, we explore the potential direct or indirect role(s) of SUMO-1 in the cellular response to misfolded α-synuclein in neurodegenerative disorders.
Topics: Animals; Autophagy; Humans; Neuroprotection; Protein Aggregates; Proteolysis; SUMO-1 Protein; alpha-Synuclein
PubMed: 26213981
DOI: 10.3390/biom5031697 -
Molecules (Basel, Switzerland) May 2023α-Synuclein aggregation under pathological conditions is one of the causes of related neurodegenerative diseases. PROTACs (proteolysis targeting chimeras) are...
α-Synuclein aggregation under pathological conditions is one of the causes of related neurodegenerative diseases. PROTACs (proteolysis targeting chimeras) are bifunctional small molecules that induce a post-translational erasure of proteins via the ubiquitination of target proteins by E3 ubiquitin ligase and subsequent proteasomal degradation. However, few research studies have been conducted for targeted protein degradation of α-synuclein aggregates. In this article, we have designed and synthesized a series of small-molecule degraders - based on a known α-synuclein aggregation inhibitor sery384. In silico docking studies of sery384 with α-synuclein aggregates were accomplished to ensure that the compounds bound to α-synuclein aggregates specifically. The protein level of α-synuclein aggregates was determined to evaluate the degradation efficiency of PROTAC molecules on α-synuclein aggregates in vitro. The results show that compound had the most significant degradation effect, with DC of 5.049 μM, and could induce the degradation of α-synuclein aggregates in a time- and dose-dependent manner in vitro. Furthermore, compound could inhibit the elevation of the ROS level caused by overexpression and aggregation of α-synuclein and protect H293T cells from α-synuclein toxicity. Conclusively, our results provide a new class of small-molecule degraders and an experimental basis for the treatment of α-synuclein related neurodegenerative diseases.
Topics: Proteolysis; alpha-Synuclein; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 37298935
DOI: 10.3390/molecules28114458 -
Cell Death & Disease Feb 2020Aggregation of alpha-synuclein (αSyn) is a crucial event underlying the pathophysiology of synucleinopathies. The existence of various intracellular and extracellular...
Aggregation of alpha-synuclein (αSyn) is a crucial event underlying the pathophysiology of synucleinopathies. The existence of various intracellular and extracellular αSyn species, including cleaved αSyn, complicates the quest for an appropriate therapeutic target. Hence, to develop efficient disease-modifying strategies, it is fundamental to achieve a deeper understanding of the relevant spreading and toxic αSyn species. Here, we describe comparative and proof-of-principle approaches to determine the involvement of αSyn fragments in intercellular spreading. We demonstrate that two different αSyn fragments (1-95 and 61-140) fulfill the criteria of spreading species. They efficiently instigate formation of proteinase-K-resistant aggregates from cell-endogenous full-length αSyn, and drive it into different aggregation pathways. The resulting aggregates induce cellular toxicity. Strikingly, these aggregates are only detectable by specific antibodies. Our results suggest that αSyn fragments might be relevant not only for spreading, but also for aggregation-fate determination and differential strain formation.
Topics: Cell Line; Extracellular Space; Gene Knockout Techniques; Humans; Neurons; Peptide Fragments; Protein Aggregates; Protein Aggregation, Pathological; Protein Domains; Protein Transport; Recombinant Proteins; alpha-Synuclein
PubMed: 32015326
DOI: 10.1038/s41419-020-2285-7 -
Colloids and Surfaces. B, Biointerfaces Jun 2018The assembly and accumulation of α-synuclein fibrils are implicated in the development of several neurodegenerative disorders including multiple system atrophy and...
The assembly and accumulation of α-synuclein fibrils are implicated in the development of several neurodegenerative disorders including multiple system atrophy and Parkinson's disease. Pre-existing α-synuclein fibrils can recruit and convert soluble non-fibrillar α-synuclein to the fibrillar form similar to what is observed in prion diseases. This raises concerns regarding attachment of fibrillary α-synuclein to medical instruments and subsequent exposure of patients to α-synuclein similar to what has been observed in iatrogenic transmission of prions. Here, we evaluated adsorption and desorption of α-synuclein to two surfaces: stainless steel and a gold surface coated with a 11-Amino-1-undecanethiol hydrochloride self-assembled-monolayer (SAM) using in-situ combinatorial quartz crystal microbalance with dissipation and spectroscopic ellipsometry. α-Synuclein was found to attach to both surfaces, however, increased α-synuclein adsorption was observed onto the positively charged SAM surface compared to the stainless steel surface. Dynamic light scattering data showed that larger α-synuclein fibrils were preferentially attached to the stainless steel surface when compared with the distributions in the original α-synuclein solution and on the SAM surface. We determined that after attachment, introduction of a 1N NaOH solution could completely remove α-synuclein adsorbed on the stainless steel surface while α-synuclein was retained on the SAM surface. Our results indicate α-synuclein can bind to multiple surface types and that decontamination is surface-dependent.
Topics: Protein Conformation; Stainless Steel; Surface Properties; alpha-Synuclein
PubMed: 29550546
DOI: 10.1016/j.colsurfb.2018.03.011 -
Biochimica Et Biophysica Acta Apr 2012The protein alpha-synuclein is considered to play a major role in the etiology of Parkinson's disease. Because it is found in a classic amyloid fibril form within the... (Review)
Review
The protein alpha-synuclein is considered to play a major role in the etiology of Parkinson's disease. Because it is found in a classic amyloid fibril form within the characteristic intra-neuronal Lewy body deposits of the disease, aggregation of the protein is thought to be of critical importance, but the context in which the protein undergoes aggregation within cells remains unknown. The normal function of synucleins is poorly understood, but appears to involve membrane interactions, and in particular reversible binding to synaptic vesicle membranes. Structural studies of different states of alpha-synuclein, in the absence and presence of membranes or membrane mimetics, have led to models of how membrane-bound forms of the protein may contribute both to functional properties of the protein, as well as to membrane-induced self-assembly and aggregation. This article reviews this area, with a focus on a particular model that has emerged in the past few years. This article is part of a Special Issue entitled: Protein Folding in Membranes.
Topics: Animals; Cell Membrane; Humans; Models, Biological; Protein Folding; Protein Structure, Quaternary; alpha-Synuclein
PubMed: 21945884
DOI: 10.1016/j.bbamem.2011.09.008 -
Biophysical Journal Mar 2021Aggregates of misfolded α-synuclein are a distinctive feature of Parkinson's disease. Small oligomers of α-synuclein are thought to be an important neurotoxic agent,...
Aggregates of misfolded α-synuclein are a distinctive feature of Parkinson's disease. Small oligomers of α-synuclein are thought to be an important neurotoxic agent, and α-synuclein aggregates exhibit prion-like behavior, propagating misfolding between cells. α-Synuclein is internalized by both passive diffusion and active uptake mechanisms, but how uptake varies with the size of the oligomer is less clear. We explored how α-synuclein internalization into live SH-SY5Y cells varied with oligomer size by comparing the uptake of fluorescently labeled monomers to that of engineered tandem dimers and tetramers. We found that these α-synuclein constructs were internalized primarily through endocytosis. Oligomer size had little effect on their internalization pathway, whether they were added individually or together. Measurements of co-localization of the α-synuclein constructs with fluorescent markers for early endosomes and lysosomes showed that most of the α-synuclein entered endocytic compartments, in which they were probably degraded. Treatment of the cells with the Pitstop inhibitor suggested that most of the oligomers were internalized by the clathrin-mediated pathway.
Topics: Biological Transport; Endocytosis; Humans; Lysosomes; alpha-Synuclein
PubMed: 33515601
DOI: 10.1016/j.bpj.2020.12.031 -
Translational Neurodegeneration 2020α-Synuclein is a small soluble protein, whose physiological function in the healthy brain is poorly understood. Intracellular inclusions of α-synuclein, referred to as... (Review)
Review
BACKGROUND
α-Synuclein is a small soluble protein, whose physiological function in the healthy brain is poorly understood. Intracellular inclusions of α-synuclein, referred to as Lewy bodies (LBs), are pathological hallmarks of α-synucleinopathies, such as Parkinson's disease (PD) or dementia with Lewy bodies (DLB).
MAIN BODY
Understanding of the molecular basis as well as the factors or conditions promoting α-synuclein misfolding and aggregation is an important step towards the comprehension of pathological mechanism of α-synucleinopathies and for the development of efficient therapeutic strategies. Based on the conversion and aggregation mechanism of α-synuclein, novel diagnostic tests, such as protein misfolding seeded conversion assays, e.g. the real-time quaking-induced conversion (RT-QuIC), had been developed. In diagnostics, α-synuclein RT-QuIC exhibits a specificity between 82 and 100% while the sensitivity varies between 70 and 100% among different laboratories. In addition, the α-synuclein RT-QuIC can be used to study the α-synuclein-seeding-characteristics of different α-synucleinopathies and to differentiate between DLB and PD.
CONCLUSION
The variable diagnostic accuracy of current α-synuclein RT-QuIC occurs due to different protocols, cohorts and material etc.. An impact of micro-environmental factors on the α-synuclein aggregation and conversion process and the occurrence and detection of differential misfolded α-synuclein types or strains might underpin the clinical heterogeneity of α-synucleinopathies
Topics: Animals; Cellular Microenvironment; Humans; Proteostasis Deficiencies; Synucleinopathies; alpha-Synuclein
PubMed: 31988747
DOI: 10.1186/s40035-019-0181-9 -
Biomolecules Aug 2022α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson's disease. Aggregated α-synuclein can impair both synaptic functioning... (Review)
Review
α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson's disease. Aggregated α-synuclein can impair both synaptic functioning and axonal transport. However, understanding the pathological role that α-synuclein plays at a cellular level is complicated as existing findings are multifaceted and dependent on the mutation, the species, and the quantity of the protein that is involved. This systematic review aims to stratify the research findings to develop a more comprehensive understanding of the role of aggregated α-synuclein on synaptic and axonal proteins in Parkinson's disease models. A literature search of the PubMed, Scopus, and Web of Science databases was conducted and a total of 39 studies were included for analysis. The review provides evidence for the dysregulation or redistribution of synaptic and axonal proteins due to α-synuclein toxicity. However, due to the high quantity of variables that were used in the research investigations, it was challenging to ascertain exactly what effect α-synuclein has on the expression of the proteins. A more standardized experimental approach regarding the variables that are employed in future studies is crucial so that existing literature can be consolidated. New research involving aggregated α-synuclein at the synapse and regarding axonal transport could be advantageous in guiding new treatment solutions.
Topics: Axons; Humans; Lewy Bodies; Parkinson Disease; Synapses; alpha-Synuclein
PubMed: 36139038
DOI: 10.3390/biom12091199