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Metallomics : Integrated Biometal... Apr 2016Alpha-synuclein has long been studied due to its involvement in the progression of Parkinson's disease (PD), a common neurodegenerative disorder, although a consensus on... (Review)
Review
Alpha-synuclein has long been studied due to its involvement in the progression of Parkinson's disease (PD), a common neurodegenerative disorder, although a consensus on the exact function of this protein is elusive. This protein shows remarkable structural plasticity and this property is important for both correct cellular function and pathological progression of PD. Formation of intracellular oligomeric species within the substantia nigra correlates with disease progression and it has been proposed that formation of a partially folded intermediate is key to the initiation of the fibrillisation process. Many factors can influence changes in the structure of alpha-synuclein such as disease mutations and interaction with metals and neurotransmitters. High concentrations of both dopamine and metals are present in the substantia nigra making this an ideal location for both the structural alteration of alpha-synuclein and the production of toxic oxygen species. The recent proposal that alpha-synuclein is a ferrireductase is important as it can possibly catalyse the formation of such reactive species and as a result exacerbate neurodegeneration.
Topics: Dopamine; Humans; Iron; Metals; Mutation; Protein Aggregates; alpha-Synuclein
PubMed: 26864076
DOI: 10.1039/c6mt00026f -
Molecular Neurobiology Apr 2013The discovery of α-synuclein has had profound implications concerning our understanding of Parkinson's disease (PD) and other neurodegenerative disorders characterized... (Review)
Review
The discovery of α-synuclein has had profound implications concerning our understanding of Parkinson's disease (PD) and other neurodegenerative disorders characterized by α-synuclein accumulation. In fact, as compared with pre-α-synuclein times, a "new" PD can now be described as a whole-body disease in which a progressive spreading of α-synuclein pathology underlies a wide spectrum of motor as well as nonmotor clinical manifestations. Not only is α-synuclein accumulation a pathological hallmark of human α-synucleinopathies but increased protein levels are sufficient to trigger neurodegenerative processes. α-Synuclein elevations could also be a mechanism by which disease risk factors (e.g., aging) increase neuronal vulnerability to degeneration. An important corollary to the role of enhanced α-synuclein in PD pathogenesis is the possibility of developing α-synuclein-based biomarkers and new therapeutics aimed at suppressing α-synuclein expression. The use of in vitro and in vivo experimental models, including transgenic mice overexpressing α-synuclein and animals with viral vector-mediated α-synuclein transduction, has helped clarify pathogenetic mechanisms and therapeutic strategies involving α-synuclein. These models are not devoid of significant limitations, however. Therefore, further pursuit of new clues on the cause and treatment of PD in this post-α-synuclein era would benefit substantially from the development of improved research paradigms of α-synuclein elevation.
Topics: Animals; Animals, Genetically Modified; Biomarkers; Disease Models, Animal; Gene Expression Regulation; Genetic Vectors; Haplorhini; Humans; Lentivirus; Mice; Neurodegenerative Diseases; Rats; Treatment Outcome; alpha-Synuclein
PubMed: 22944910
DOI: 10.1007/s12035-012-8329-y -
Current Neuropharmacology 2016Alpha-Synuclein is found in the neuronal cells but its native function is not well known. While α -synuclein is an intrinsically disordered protein that adopts a... (Review)
Review
Alpha-Synuclein is found in the neuronal cells but its native function is not well known. While α -synuclein is an intrinsically disordered protein that adopts a helical conformation upon membrane binding, numerous studies have shown that oligomeric β-forms of this protein are cytotoxic. This response to misfolded species contributes to Parkinson's Disease etiology and symptoms. The resulting amyloid fibrils are an established diagnostic in Parkinson's Disease. In this review, we focus on strategies that have been used to inhibit the amyloidogenesis of α -synuclein either by stabilizing the native state, or by redirecting the pathway to less toxic aggregates. Small molecules such as polyphenols, peptides as well as large proteins have proven effective at protecting cells against the cytotoxicity of α-synuclein. These strategies may lead to the development of therapeutic agents that could prove useful in combating this disease.
Topics: Amyloid; Amyloidosis; Animals; Humans; Mutation; Parkinson Disease; Protein Folding; alpha-Synuclein
PubMed: 26517049
DOI: 10.2174/1570159x13666151030103153 -
Trends in Biochemical Sciences May 2019The presynaptic protein α-synuclein (aSyn) is an 'intrinsically disordered protein' that is highly dynamic in conformation. Transient intramolecular interactions... (Review)
Review
The presynaptic protein α-synuclein (aSyn) is an 'intrinsically disordered protein' that is highly dynamic in conformation. Transient intramolecular interactions between its charged N and C termini, and between its hydrophobic region and the C terminus, prevent self-association. These interactions inhibit the formation of insoluble inclusions, which are the pathological hallmark of Parkinson's disease and many other synucleinopathies. This review discusses how these intramolecular interactions are influenced by the specific environment aSyn is in. We discuss how charge, pH, calcium, and salt affect the physiological structure of monomeric aSyn, and how they may favour the formation of toxic structures. The more we understand the dynamic conformations of aSyn, the better we can design desperately needed therapeutics to prevent disease progression.
Topics: Animals; Humans; Hydrophobic and Hydrophilic Interactions; Protein Conformation; alpha-Synuclein
PubMed: 30527975
DOI: 10.1016/j.tibs.2018.11.005 -
Current Neurology and Neuroscience... Feb 2019We provide an overview about unbiased screens to identify modifiers of alpha-synuclein (αSyn)-induced toxicity, present the models and the libraries that have been used... (Review)
Review
PURPOSE OF REVIEW
We provide an overview about unbiased screens to identify modifiers of alpha-synuclein (αSyn)-induced toxicity, present the models and the libraries that have been used for screening, and describe how hits from primary screens were selected and validated.
RECENT FINDINGS
Screens can be classified as either genetic or chemical compound modifier screens, but a few screens do not fit this classification. Most screens addressing αSyn-induced toxicity, including genome-wide overexpressing and deletion, were performed in yeast. More recently, newer methods such as CRISPR-Cas9 became available and were used for screening purposes. Paradoxically, given that αSyn-induced toxicity plays a role in neurological diseases, there is a shortage of human cell-based models for screening. Moreover, most screens used mutant or fluorescently tagged forms of αSyn and only very few screens investigated wild-type αSyn. Particularly, no genome-wide αSyn toxicity screen in human dopaminergic neurons has been published so far. Most unbiased screens for modifiers of αSyn toxicity were performed in yeast, and there is a lack of screens performed in human and particularly dopaminergic cells.
Topics: Animals; Dopaminergic Neurons; Humans; alpha-Synuclein
PubMed: 30739256
DOI: 10.1007/s11910-019-0925-z -
Cell and Tissue Research Jul 2018In 2017, it was 200 years since James Parkinson published 'An Essay on the Shaking Palsy' and 20 years since α-synuclein aggregation came to the fore. In 1998,... (Review)
Review
In 2017, it was 200 years since James Parkinson published 'An Essay on the Shaking Palsy' and 20 years since α-synuclein aggregation came to the fore. In 1998, multiple system atrophy joined Parkinson's disease and dementia with Lewy bodies as the third major synucleinopathy. Here, we describe the work that led to the identification of α-synuclein in Lewy bodies, Lewy neurites and Papp-Lantos bodies. We also review some of the findings reported since 1997.
Topics: Amino Acid Sequence; Animals; Humans; Lewy Bodies; Nerve Degeneration; Protein Aggregates; alpha-Synuclein
PubMed: 29119326
DOI: 10.1007/s00441-017-2706-9 -
Proceedings of the National Academy of... Aug 2021α-Synuclein (α-syn) is central to the pathogenesis of Parkinson's disease (PD), in which its nonfunctional oligomers accumulate and result in abnormal...
α-Synuclein (α-syn) is central to the pathogenesis of Parkinson's disease (PD), in which its nonfunctional oligomers accumulate and result in abnormal neurotransmission. The normal physiological function of this intrinsically disordered protein is still unclear. Although several previous studies demonstrated α-syn's role in various membrane fusion steps, they produced conflicting outcomes regarding vesicular secretion. Here, we assess α-syn's role in directly regulating individual exocytotic release events. We studied the micromillisecond dynamics of single recombinant fusion pores, the crucial kinetic intermediate of membrane fusion that tightly regulates the vesicular secretion in different cell types. α-Syn accessed v-SNARE within the trans-SNARE complex to form an inhibitory complex. This activity was dependent on negatively charged phospholipids and resulted in decreased open probability of individual pores. The number of trans-SNARE complexes influenced α-syn's inhibitory action. Regulatory factors that arrest SNARE complexes in different assembly states differentially modulate α-syn's ability to alter fusion pore dynamics. α-Syn regulates pore properties in the presence of Munc13-1 and Munc18, which stimulate α-SNAP/NSF-resistant SNARE complex formation. In the presence of synaptotagmin1(syt1), α-syn contributes with apo-syt1 to act as a membrane fusion clamp, whereas Ca•syt1 triggered α-syn-resistant SNARE complex formation that rendered α-syn inactive in modulating pore properties. This study reveals a key role of α-syn in controlling vesicular secretion.
Topics: Hemolysin Proteins; Lab-On-A-Chip Devices; Lipids; Membranes, Artificial; SNARE Proteins; alpha-Synuclein
PubMed: 34413185
DOI: 10.1073/pnas.2021742118 -
Current Protein & Peptide Science 2018Alpha synuclein (α-syn) belongs to a class of proteins which are commonly considered to play a detrimental role in neuronal survival. This assumption is based on the... (Review)
Review
Alpha synuclein (α-syn) belongs to a class of proteins which are commonly considered to play a detrimental role in neuronal survival. This assumption is based on the occurrence of a severe neuronal degeneration in patients carrying a multiplication of the α-syn gene (SNCA) and in a variety of experimental models, where overexpression of α-syn leads to cell death and neurological impairment. In these conditions, a higher amount of normally structured α-syn produces a damage, which is even worse compared with that produced by α-syn owning an abnormal structure (as occurring following point gene mutations). In line with this, knocking out the expression of α-syn is reported to protect from specific neurotoxins such as 1-methyl, 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP). In the present review we briefly discuss these well-known detrimental effects but we focus on findings showing that, in specific conditions α-syn is beneficial for cell survival. This occurs during methamphetamine intoxication which is counteracted by endogenous α-syn. Similarly, the dysfunction of the chaperone cysteine-string protein- alpha leads to cell pathology which is counteracted by over-expressing α-syn. In line with this, an increased expression of α-syn protects against oxidative damage produced by dopamine. Remarkably, when the lack of α-syn is combined with a depletion of β- and γ- synucleins, alterations in brain structure and function occur. This review tries to balance the evidence showing a beneficial effect with the bulk of data reporting a detrimental effect of endogenous α-syn. The specific role of α-syn as a chaperone protein is discussed to explain such a dual effect.
Topics: Animals; Apoptosis; Brain; Gene Expression; Humans; Nerve Degeneration; Neurons; Neuroprotection; Oxidative Stress; Signal Transduction; alpha-Synuclein
PubMed: 29150919
DOI: 10.2174/1389203718666171117110028 -
Current Protein & Peptide Science Oct 2008Alpha-synuclein is an abundant presynaptic brain protein, misfolding, aggregation and fibrillation of which are implicated as critical factors in several... (Review)
Review
Alpha-synuclein is an abundant presynaptic brain protein, misfolding, aggregation and fibrillation of which are implicated as critical factors in several neurodegenerative diseases. The list of the well-known synucleinopathies includes such devastating disorders as Parkinson's disease, Lewy body variant of Alzheimer's disease, diffuse Lewy body disease, dementia with Lewy bodies, multiple system atrophy, and neurodegeneration with brain iron accumulation type I. The precise functions of alpha-synuclein remain elusive, but there are evidence indicating its involvement in regulation vesicular release and/or turnover and synaptic function in the central nervous system. It might play a role in neuronal plasticity responses, bind fatty acids, regulate certain enzymes, transporters, and neurotransmitter vesicles, be involved in neuronal survival and even can act as a molecular chaperone. Structurally, alpha-synuclein is an illustrative member of the rapidly growing family of natively unfolded (or intrinsically disordered) proteins and considerable knowledge has been accumulated about its structural properties and conformational behavior. The molecular mechanisms underlying misfolding, aggregation and fibrillation of alpha-synuclein and the role of various environmental and genetic factors in stimulation and inhibition of these processes are relatively well understood. Here, the main structural features of alpha-synuclein, its functions, and involvement in various human diseases are summarized providing a foundation for better understanding of the biochemistry, biophysics and neuropathology of alpha-synuclein aggregation.
Topics: Amino Acid Sequence; Amino Acid Substitution; Animals; Humans; Models, Molecular; Molecular Sequence Data; Neurodegenerative Diseases; Point Mutation; Protein Folding; Protein Processing, Post-Translational; alpha-Synuclein
PubMed: 18855701
DOI: 10.2174/138920308785915218 -
Biomolecules Apr 2015Parkinson's Disease (PD) is a complex neurodegenerative disorder classically characterized by movement impairment. Pathologically, the most striking features of PD are... (Review)
Review
Parkinson's Disease (PD) is a complex neurodegenerative disorder classically characterized by movement impairment. Pathologically, the most striking features of PD are the loss of dopaminergic neurons and the presence of intraneuronal protein inclusions primarily composed of alpha-synuclein (α-syn) that are known as Lewy bodies and Lewy neurites in surviving neurons. Though the mechanisms underlying the progression of PD pathology are unclear, accumulating evidence suggests a prion-like spreading of α-syn pathology. The intracellular homeostasis of α-syn requires the proper degradation of the protein by three mechanisms: chaperone-mediated autophagy, macroautophagy and ubiquitin-proteasome. Impairment of these pathways might drive the system towards an alternative clearance mechanism that could involve its release from the cell. This increased release to the extracellular space could be the basis for α-syn propagation to different brain areas and, ultimately, for the spreading of pathology and disease progression. Here, we review the interplay between α-syn degradation pathways and its intercellular spreading. The understanding of this interplay is indispensable for obtaining a better knowledge of the molecular basis of PD and, consequently, for the design of novel avenues for therapeutic intervention.
Topics: Animals; Autophagy; Humans; Parkinson Disease; Proteolysis; alpha-Synuclein
PubMed: 25874605
DOI: 10.3390/biom5020435