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Cold Spring Harbor Perspectives in... Mar 2018α-Synuclein is an abundant neuronal protein that is highly enriched in presynaptic nerve terminals. Genetics and neuropathology studies link α-synuclein to Parkinson's... (Review)
Review
α-Synuclein is an abundant neuronal protein that is highly enriched in presynaptic nerve terminals. Genetics and neuropathology studies link α-synuclein to Parkinson's disease (PD) and other neurodegenerative disorders. Accumulation of misfolded oligomers and larger aggregates of α-synuclein defines multiple neurodegenerative diseases called synucleinopathies, but the mechanisms by which α-synuclein acts in neurodegeneration are unknown. Moreover, the normal cellular function of α-synuclein remains debated. In this perspective, we review the structural characteristics of α-synuclein, its developmental expression pattern, its cellular and subcellular localization, and its function in neurons. We also discuss recent progress on secretion of α-synuclein, which may contribute to its interneuronal spread in a prion-like fashion, and describe the neurotoxic effects of α-synuclein that are thought to be responsible for its role in neurodegeneration.
Topics: Animals; Humans; Mice; Mice, Transgenic; Neurons; Parkinson Disease; Synapses; alpha-Synuclein
PubMed: 28108534
DOI: 10.1101/cshperspect.a024091 -
Neuron May 2023Pathogenic α-synuclein and tau are critical drivers of neurodegeneration, and their mutations cause neuronal loss in patients. Whether the underlying preferential...
Pathogenic α-synuclein and tau are critical drivers of neurodegeneration, and their mutations cause neuronal loss in patients. Whether the underlying preferential neuronal vulnerability is a cell-type-intrinsic property or a consequence of increased expression levels remains elusive. Here, we explore cell-type-specific α-synuclein and tau expression in human brain datasets and use deep phenotyping as well as brain-wide single-cell RNA sequencing of >200 live neuron types in fruit flies to determine which cellular environments react most to α-synuclein or tau toxicity. We detect phenotypic and transcriptomic evidence of differential neuronal vulnerability independent of α-synuclein or tau expression levels. Comparing vulnerable with resilient neurons in Drosophila enabled us to predict numerous human neuron subtypes with increased intrinsic susceptibility to pathogenic α-synuclein or tau. By uncovering synapse- and Ca homeostasis-related genes as tau toxicity modifiers, our work paves the way to leverage neuronal identity to uncover modifiers of neurodegeneration-associated toxic proteins.
Topics: Humans; alpha-Synuclein; tau Proteins; Brain; Neurons; Head
PubMed: 36948206
DOI: 10.1016/j.neuron.2023.02.033 -
Nature Chemistry Aug 2020α-Synuclein (α-Syn) aggregation and amyloid formation is directly linked with Parkinson's disease pathogenesis. However, the early events involved in this process...
α-Synuclein (α-Syn) aggregation and amyloid formation is directly linked with Parkinson's disease pathogenesis. However, the early events involved in this process remain unclear. Here, using the in vitro reconstitution and cellular model, we show that liquid-liquid phase separation of α-Syn precedes its aggregation. In particular, in vitro generated α-Syn liquid-like droplets eventually undergo a liquid-to-solid transition and form an amyloid hydrogel that contains oligomers and fibrillar species. Factors known to aggravate α-Syn aggregation, such as low pH, phosphomimetic substitution and familial Parkinson's disease mutations, also promote α-Syn liquid-liquid phase separation and its subsequent maturation. We further demonstrate α-Syn liquid-droplet formation in cells. These cellular α-Syn droplets eventually transform into perinuclear aggresomes, the process regulated by microtubules. This work provides detailed insights into the phase-separation behaviour of natively unstructured α-Syn and its conversion to a disease-associated aggregated state, which is highly relevant in Parkinson's disease pathogenesis.
Topics: HeLa Cells; Humans; Hydrogen-Ion Concentration; Microscopy, Confocal; Mutagenesis, Site-Directed; Parkinson Disease; Phase Transition; Polyethylene Glycols; Protein Aggregates; Recombinant Proteins; alpha-Synuclein
PubMed: 32514159
DOI: 10.1038/s41557-020-0465-9 -
Nature Feb 2020Synucleinopathies are neurodegenerative diseases that are associated with the misfolding and aggregation of α-synuclein, including Parkinson's disease, dementia with...
Synucleinopathies are neurodegenerative diseases that are associated with the misfolding and aggregation of α-synuclein, including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Clinically, it is challenging to differentiate Parkinson's disease and multiple system atrophy, especially at the early stages of disease. Aggregates of α-synuclein in distinct synucleinopathies have been proposed to represent different conformational strains of α-synuclein that can self-propagate and spread from cell to cell. Protein misfolding cyclic amplification (PMCA) is a technique that has previously been used to detect α-synuclein aggregates in samples of cerebrospinal fluid with high sensitivity and specificity. Here we show that the α-synuclein-PMCA assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinson's disease and samples from patients with multiple system atrophy, with an overall sensitivity of 95.4%. We used a combination of biochemical, biophysical and biological methods to analyse the product of α-synuclein-PMCA, and found that the characteristics of the α-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinson's disease and multiple system atrophy. We also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggest that α-synuclein aggregates that are associated with Parkinson's disease and multiple system atrophy correspond to different conformational strains of α-synuclein, which can be amplified and detected by α-synuclein-PMCA. Our results may help to improve our understanding of the mechanism of α-synuclein misfolding and the structures of the aggregates that are implicated in different synucleinopathies, and may also enable the development of a biochemical assay to discriminate between Parkinson's disease and multiple system atrophy.
Topics: Amyloid; Brain Chemistry; Circular Dichroism; Endopeptidase K; Humans; Multiple System Atrophy; Parkinson Disease; Protein Conformation; Protein Denaturation; Protein Folding; Spectroscopy, Fourier Transform Infrared; alpha-Synuclein
PubMed: 32025029
DOI: 10.1038/s41586-020-1984-7 -
The Lancet. Neurology Aug 2015Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the α-synuclein protein in the form of Lewy bodies... (Review)
Review
Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the α-synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease. Most cases occur sporadically, but mutations in several genes, including SNCA, which encodes α-synuclein, are associated with disease development. The discovery and development of therapeutic strategies to block cell death in Parkinson's disease has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence of multiple pivotal roles of α-synuclein in the pathogenesis of Parkinson's disease has led researchers to consider the therapeutic potential of several strategies aimed at reduction of α-synuclein toxicity. We critically assess the potential of experimental therapies targeting α-synuclein, and discuss steps that need to be taken for target validation and drug development.
Topics: Animals; Drug Discovery; Humans; Parkinson Disease; alpha-Synuclein
PubMed: 26050140
DOI: 10.1016/S1474-4422(15)00006-X -
Science (New York, N.Y.) Dec 2017Oligomeric species populated during the aggregation process of α-synuclein have been linked to neuronal impairment in Parkinson's disease and related neurodegenerative...
Oligomeric species populated during the aggregation process of α-synuclein have been linked to neuronal impairment in Parkinson's disease and related neurodegenerative disorders. By using solution and solid-state nuclear magnetic resonance techniques in conjunction with other structural methods, we identified the fundamental characteristics that enable toxic α-synuclein oligomers to perturb biological membranes and disrupt cellular function; these include a highly lipophilic element that promotes strong membrane interactions and a structured region that inserts into lipid bilayers and disrupts their integrity. In support of these conclusions, mutations that target the region that promotes strong membrane interactions by α-synuclein oligomers suppressed their toxicity in neuroblastoma cells and primary cortical neurons.
Topics: Cell Line, Tumor; Cell Membrane; Cerebral Cortex; Humans; Lipid Bilayers; Mutation; Neurons; Nuclear Magnetic Resonance, Biomolecular; Parkinson Disease; Protein Aggregation, Pathological; alpha-Synuclein
PubMed: 29242346
DOI: 10.1126/science.aan6160 -
International Journal of Biological... Jul 2017Parkinson's disease (PD) is a neurological disorder marked by the presence of cytoplasmic inclusions, Lewy bodies (LBs) and Lewy neurites (LNs) as well as the... (Review)
Review
Parkinson's disease (PD) is a neurological disorder marked by the presence of cytoplasmic inclusions, Lewy bodies (LBs) and Lewy neurites (LNs) as well as the degeneration of dopamine producing neurons in the substantia nigra region of the brain. The LBs and LNs in PD are mainly composed of aggregated form of a presynaptic protein, α-synuclein (α-Syn). However, the mechanisms of α-Syn aggregation and actual aggregated species responsible for the degeneration of dopaminergic neurons have not yet been resolved. Despite the fact that α-Syn aggregation in LBs and LNs is crucial and mutations of α-Syn are associated with early onset PD, it is really a challenging task to establish a correlation between α-Syn aggregation rate and PD pathogenesis. Regardless of strong genetic contribution, PD is mostly sporadic and familial forms of the disease represent only a minor part (<10%) of all cases. The complexity in PD further increases due to the involvement of several cellular factors in the pathogenesis of the disease as well as the environmental factors associated with the risk of developing PD. Therefore, effect of these factors on α-Syn aggregation pathway and how these factors modulate the properties of wild type (WT) as well as mutated α-Syn should be collectively taken into account. The present review specifically provides an overview of recent research on α-Syn aggregation pathways and its modulation by several cellular factors potentially relevant to PD pathogenesis. We also briefly discuss about effect of environmental risk factors on α-Syn aggregation.
Topics: Amino Acid Sequence; Animals; Glycosaminoglycans; Humans; Parkinson Disease; Polyamines; Protein Aggregates; alpha-Synuclein
PubMed: 27737778
DOI: 10.1016/j.ijbiomac.2016.10.021 -
Cells Nov 2021Alpha-synucleinopathies comprise progressive neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy... (Review)
Review
Alpha-synucleinopathies comprise progressive neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). They all exhibit the same pathological hallmark, which is the formation of α-synuclein positive deposits in neuronal or glial cells. The aggregation of α-synuclein in the cell body of neurons, giving rise to the so-called Lewy bodies (LBs), is the major characteristic for PD and DLB, whereas the accumulation of α-synuclein in oligodendroglial cells, so-called glial cytoplasmic inclusions (GCIs), is the hallmark for MSA. The mechanisms involved in the intracytoplasmic inclusion formation in neuronal and oligodendroglial cells are not fully understood to date. A possible mechanism could be an impaired autophagic machinery that cannot cope with the high intracellular amount of α-synuclein. In fact, different studies showed that reduced autophagy is involved in α-synuclein aggregation. Furthermore, altered levels of different autophagy markers were reported in PD, DLB, and MSA brains. To date, the trigger point in disease initiation is not entirely clear; that is, whether autophagy dysfunction alone suffices to increase α-synuclein or whether α-synuclein is the pathogenic driver. In the current review, we discuss the involvement of defective autophagy machinery in the formation of α-synuclein aggregates, propagation of α-synuclein, and the resulting neurodegenerative processes in α-synucleinopathies.
Topics: Animals; Autophagy; Disease Models, Animal; Humans; Neurons; Oligodendroglia; Synucleinopathies; alpha-Synuclein
PubMed: 34831366
DOI: 10.3390/cells10113143 -
Experimental & Molecular Medicine Dec 2022The clinical progression of neurodegenerative diseases correlates with the spread of proteinopathy in the brain. The current understanding of the mechanism of...
The clinical progression of neurodegenerative diseases correlates with the spread of proteinopathy in the brain. The current understanding of the mechanism of proteinopathy spread is far from complete. Here, we propose that inflammation is fundamental to proteinopathy spread. A sequence variant of α-synuclein (V40G) was much less capable of fibril formation than wild-type α-synuclein (WT-syn) and, when mixed with WT-syn, interfered with its fibrillation. However, when V40G was injected intracerebrally into mice, it induced aggregate spreading even more effectively than WT-syn. Aggregate spreading was preceded by sustained microgliosis and inflammatory responses, which were more robust with V40G than with WT-syn. Oral administration of an anti-inflammatory agent suppressed aggregate spreading, inflammation, and behavioral deficits in mice. Furthermore, exposure of cells to inflammatory cytokines increased the cell-to-cell propagation of α-synuclein. These results suggest that the inflammatory microenvironment is the major driver of the spread of synucleinopathy in the brain.
Topics: Mice; Animals; alpha-Synuclein; Synucleinopathies; Brain; Neurodegenerative Diseases; Inflammation; Disease Models, Animal
PubMed: 36473937
DOI: 10.1038/s12276-022-00895-w -
Current Neurology and Neuroscience... Apr 2017Mutations in the SNCA gene, which encodes the α-synuclein protein, were the first discovered genetic causes of familial parkinsonism with Lewy pathology. To date, six... (Review)
Review
Mutations in the SNCA gene, which encodes the α-synuclein protein, were the first discovered genetic causes of familial parkinsonism with Lewy pathology. To date, six different SNCA missense mutations as well as multiplications are known to cause parkinsonism. For this review, we performed a literature search to identify all published cases of SNCA-related parkinsonism to provide an updated summary of the clinical and neuropathological features of parkinsonism due to SNCA mutations. Familial parkinsonism associated with SNCA is rare, but α-synuclein aggregation is a core feature of sporadic parkinsonism, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Research into α-synuclein and parkinsonism has impacted how we define the pathology and understand the pathogenesis of Parkinson's disease and related neurodegenerative disorders. We briefly discuss some of the lessons we have learned from research into the physiological role of α-synuclein and its pathological links to neurodegeneration and parkinsonism.
Topics: Humans; Lewy Bodies; Mutation; Parkinsonian Disorders; Phenotype; alpha-Synuclein
PubMed: 28324300
DOI: 10.1007/s11910-017-0737-y