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Biochemistry Nov 2019Secretagogin (SCGN) is a secreted calcium sensor that has emerged as a potential multifunctional protein of neuroendocrine cells. A significantly reduced level of...
Secretagogin (SCGN) is a secreted calcium sensor that has emerged as a potential multifunctional protein of neuroendocrine cells. A significantly reduced level of expression of SCGN has been reported in the hippocampus of a mouse model of Alzheimer's disease (AD) and in Parkinson's patients, although the biochemical implications and mechanistic underpinnings of the altered SCGN expression in neurodegenerative diseases remain unknown. We have pursued the interaction of SCGN with α-synuclein that we discovered in impartial pull-down analyses to decode the SCGN interactome. SCGN physically binds α-synuclein and rescues it from detrimental fibrillation. Correspondingly, it is observed that a significant reduction in the cytotoxicity of α-synuclein fibrils is caused by SCGN. We map these antifibrillar attributes to the central region and C-terminal domain of SCGN, while the N-terminal domain is not essential for this activity. On the basis of these results, a broader neuroprotective function of SCGN by proficient chaperone action is proposed. An intriguing correlation of this interaction with a reduced level of expression of SCGN in neurodegenerative diseases shall inspire further studies of the physiological role of SCGN in precluding pathological protein aggregation.
Topics: Animals; Cell Line; Mice; Models, Molecular; Protein Aggregation, Pathological; Protein Binding; Protein Interaction Domains and Motifs; Secretagogins; alpha-Synuclein
PubMed: 31617346
DOI: 10.1021/acs.biochem.9b00656 -
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 -
Journal of Neurochemistry May 2016The aggregation of alpha synuclein (α-syn) is a neuropathological feature that defines a spectrum of disorders collectively termed synucleinopathies, and of these,... (Review)
Review
The aggregation of alpha synuclein (α-syn) is a neuropathological feature that defines a spectrum of disorders collectively termed synucleinopathies, and of these, Parkinson's disease (PD) is arguably the best characterized. Aggregated α-syn is the primary component of Lewy bodies, the defining pathological feature of PD, while mutations or multiplications in the α-syn gene result in familial PD. The high correlation between α-syn burden and PD has led to the hypothesis that α-syn aggregation produces toxicity through a gain-of-function mechanism. However, α-syn has been implicated to function in a diverse range of essential cellular processes such as the regulation of neurotransmission and response to cellular stress. As such, an alternative hypothesis with equal explanatory power is that the aggregation of α-syn results in toxicity because of a toxic loss of necessary α-syn function, following sequestration of functional forms α-syn into insoluble protein aggregates. Within this review, we will provide an overview of the literature linking α-syn to PD and the knowledge gained from current α-syn-based animal models of PD. We will then interpret these data from the viewpoint of the α-syn loss-of-function hypothesis and provide a potential mechanistic model by which loss of α-syn function could result in at least some of the neurodegeneration observed in PD. By providing an alternative perspective on the etiopathogenesis of PD and synucleinopathies, this may reveal alternative avenues of research in order to identify potential novel therapeutic targets for disease modifying strategies. The correlation between α-synuclein burden and Parkinson's disease pathology has led to the hypothesis that α-synuclein aggregation produces toxicity through a gain-of-function mechanism. However, in this review, we discuss data supporting the alternative hypothesis that the aggregation of α-synuclein results in toxicity because of loss of necessary α-synuclein function at the presynaptic terminal, following sequestration of functional forms of α-synuclein into aggregates.
Topics: Animals; Antiparkinson Agents; Humans; Neurons; Parkinson Disease; alpha-Synuclein
PubMed: 26852372
DOI: 10.1111/jnc.13570 -
BioFactors (Oxford, England) 2024α-Synuclein (αS) aggregation is the main neurological hallmark of a group of debilitating neurodegenerative disorders, collectively referred to as synucleinopathies,... (Review)
Review
α-Synuclein (αS) aggregation is the main neurological hallmark of a group of debilitating neurodegenerative disorders, collectively referred to as synucleinopathies, of which Parkinson's disease is the most prevalent. αS oligomers formed during the initial stages of aggregation are considered key pathogenic drivers of disease onset and progression, standing as privileged targets for therapeutic intervention and diagnosis. However, the structure of αS oligomers and the mechanistic basis of oligomer to fibril conversion are yet poorly understood, thereby precluding the rational formulation of strategies aimed at targeting oligomeric species. In this review, we delve into the recent advances in the structural and mechanistic characterization of αS oligomers. We also discuss how these advances are transforming our understanding of these elusive species and paving the way for oligomer-targeting therapeutics and diagnosis.
Topics: alpha-Synuclein; Humans; Parkinson Disease; Protein Multimerization; Protein Aggregation, Pathological; Protein Aggregates
PubMed: 38063360
DOI: 10.1002/biof.2021 -
Cell Reports Jan 2022Alpha-synuclein (αS) is causally involved in the development of Parkinson disease (PD); however, its role in normal vertebrate physiology has remained unknown. Recent...
Alpha-synuclein (αS) is causally involved in the development of Parkinson disease (PD); however, its role in normal vertebrate physiology has remained unknown. Recent studies demonstrate that αS is induced by noroviral infection in the enteric nervous system of children and protects mice against lethal neurotropic viral infection. Additionally, αS is a potent chemotactic activator of phagocytes. In this report, using both wild-type and αS knockout mice, we show that αS is a critical mediator of inflammatory and immune responses. αS is required for the development of a normal inflammatory response to bacterial peptidoglycan introduced into the peritoneal cavity as well as antigen-specific and T cell responses following intraperitoneal immunization. Furthermore, we show that neural cells are the sources of αS required for immune competence. Our report supports the hypothesis that αS accumulates within the nervous system of PD individuals because of an inflammatory/immune response.
Topics: Animals; Brain; Female; Humans; Immunity; Mice; Mice, Inbred C57BL; Mice, Knockout; Nervous System; Neurons; Toll-Like Receptor 4; alpha-Synuclein
PubMed: 35021075
DOI: 10.1016/j.celrep.2021.110090 -
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 -
ACS Chemical Neuroscience Mar 2019Recent expeditious advances in the determination of the 3-D structure of fibrils of alpha-synuclein, the intrinsically disordered protein associated with the... (Review)
Review
Recent expeditious advances in the determination of the 3-D structure of fibrils of alpha-synuclein, the intrinsically disordered protein associated with the neurodegenerative Parkinson's disease (PD), have identified amino acid contacts that form the fibril's inter-protofilament interface. The residues that constitute this "steric zipper" interface determine the morphology of the fibrils as well as toxicity of the oligomeric building units or "kernels" which lead to the formation of the protofilaments. The zipper interface houses key amino acid residues involved in familial PD that can be targeted by drug design.
Topics: Amino Acid Sequence; Amyloid; Animals; Cryoelectron Microscopy; Humans; Protein Structure, Secondary; alpha-Synuclein
PubMed: 30785257
DOI: 10.1021/acschemneuro.9b00090 -
Trends in Molecular Medicine Jun 2013The aggregation of the protein alpha-synuclein (α-SYN) is believed to be a critical event in Parkinson's disease (PD). α-SYN is characterized by a remarkable... (Review)
Review
The aggregation of the protein alpha-synuclein (α-SYN) is believed to be a critical event in Parkinson's disease (PD). α-SYN is characterized by a remarkable conformational plasticity, adopting different conformations depending on the environment. In vitro, α-SYN lacks a well-defined structure. Therefore, it was classified as an 'intrinsically disordered protein'. A debate has recently begun over how α-SYN behaves in the cell: is it an intrinsically disordered protein or a stable tetramer with a low propensity for aggregation? In this review, we discuss the aggregation of α-SYN and describe factors that influence this process and their potential relevance in PD pathogenesis. We address the ways in which aggregated α-SYN mediates toxicity and might lead to PD, and propose possible therapeutic strategies.
Topics: Animals; Humans; Parkinson Disease; Protein Conformation; alpha-Synuclein
PubMed: 23648364
DOI: 10.1016/j.molmed.2013.04.002 -
Molecular Neurobiology Apr 2013The toxicity of α-synuclein in the neuropathology of Parkinson's disease which includes its hallmark aggregation has been studied scrupulously in the last decade.... (Review)
Review
The toxicity of α-synuclein in the neuropathology of Parkinson's disease which includes its hallmark aggregation has been studied scrupulously in the last decade. Although little is known regarding the normal functions of α-synuclein, its association with membrane phospholipids suggests its potential role in signaling pathways. Following extensive evidences for its nuclear localization, we and others recently demonstrated DNA binding activity of α-synuclein that modulates its conformation as well as aggregation properties. Furthermore, we also underscored the similarities among various amyloidogenic proteins involved in neurodegenerative diseases including amyloid beta peptides and tau. Our more recent studies show that α-synuclein is glycated and glycosylated both in vitro and in neurons, significantly affecting its folding, oligomeric, and DNA binding properties. Glycated α-synuclein causes increased genome damage both via its direct interaction with DNA and by increased generation of reactive oxygen species as glycation byproduct. In this review, we discuss the mechanisms of glycation and other posttranslational modifications of α-synuclein, including phosphorylation and nitration, and their role in neuronal death in Parkinson's disease.
Topics: Animals; Cell Death; Glycation End Products, Advanced; Glycosylation; Humans; Parkinson Disease; Phosphorylation; Protein Binding; Protein Folding; alpha-Synuclein
PubMed: 22923367
DOI: 10.1007/s12035-012-8328-z -
Biological Chemistry Sep 2020α-Synuclein fibrillation is now regarded as a major pathogenic process in Parkinson's disease and its proteinaceous deposits are also detected in other neurological...
α-Synuclein fibrillation is now regarded as a major pathogenic process in Parkinson's disease and its proteinaceous deposits are also detected in other neurological disorders including Alzheimer's disease. Therefore anti-amyloidegenic compounds may delay or prevent the progression of synucleinopathies disease. Molecular chaperones are group of proteins which mediate correct folding of proteins by preventing unsuitable interactions which may lead to aggregation. The objective of this study was to investigate the anti-amyloidogenic effect of molecular chaperone artemin on α-synuclein. As the concentration of artemin was increased up to 4 μg/ml, a decrease in fibril formation of α-synuclein was observed using thioflavin T (ThT) fluorescence and congo red (CR) assay. Transmission electron microscopy (TEM) images also demonstrated a reduction in fibrils in the presence of artemin. The secondary structure of α-synuclein was similar to its native form prior to fibrillation when incubated with artemin. A cell-based assay has shown that artemin inhibits α-synuclein aggregation and reduce cytotoxicity, apoptosis and reactive oxygen species (ROS) production. Our results revealed that artemin has efficient chaperon activity for preventing α-synuclein fibril formation and toxicity.
Topics: Apoptosis; Cell Line, Tumor; Cell Survival; Humans; Molecular Chaperones; Nerve Tissue Proteins; Protein Aggregates; Protein Aggregation, Pathological; Reactive Oxygen Species; alpha-Synuclein
PubMed: 32673279
DOI: 10.1515/hsz-2019-0446