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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 -
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 -
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 -
Progress in Brain Research 2020Alpha-synuclein (aSyn) was identified as the main component of inclusions that define synucleinopathies more than 20 years ago. Since then, aSyn has been extensively... (Review)
Review
Alpha-synuclein (aSyn) was identified as the main component of inclusions that define synucleinopathies more than 20 years ago. Since then, aSyn has been extensively studied in an attempt to unravel its roles in both physiology and pathology. Today, studying the mechanisms of aSyn toxicity remains in the limelight, leading to the identification of novel pathways involved in pathogenesis. In this chapter, we address the molecular mechanisms involved in synucleinopathies, from aSyn misfolding and aggregation to the various cellular effects and pathologies associated. In particular, we review our current understanding of the mechanisms involved in the spreading of aSyn between different cells, from the periphery to the brain, and back. Finally, we also review recent studies on the contribution of inflammation and the gut microbiota to pathology in synucleinopathies. Despite significant advances in our understanding of the molecular mechanisms involved, we still lack an integrated understanding of the pathways leading to neurodegeneration in PD and other synucleinopathies, compromising our ability to develop novel therapeutic strategies.
Topics: Animals; Humans; Inflammation; Microbiota; Synucleinopathies; alpha-Synuclein
PubMed: 32247376
DOI: 10.1016/bs.pbr.2019.10.005 -
Neurobiology of Disease Apr 2016α-Synuclein is a conserved, abundantly expressed protein that is partially localized in pre-synaptic terminals in the central nervous system. The precise biological... (Review)
Review
α-Synuclein is a conserved, abundantly expressed protein that is partially localized in pre-synaptic terminals in the central nervous system. The precise biological function(s) and structure of α-synuclein are under investigation. Recently, the native conformation and the presence of naturally occurring multimeric assemblies have come under debate. These are important deliberations because α-synuclein assembles into highly organized amyloid-like fibrils and non-amyloid amorphous aggregates that constitute the neuronal inclusions in Parkinson's disease and related disorders. Therefore understanding the nature of the native and pathological conformations is pivotal from the standpoint of therapeutic interventions that could maintain α-synuclein in its physiological state. In this review, we will discuss the existing evidence that define the physiological states of α-synuclein and highlight how the inherent structural flexibility of this protein may be important in health and disease.
Topics: Animals; Humans; Models, Chemical; Nonlinear Dynamics; Protein Conformation; alpha-Synuclein
PubMed: 26747212
DOI: 10.1016/j.nbd.2015.12.018 -
Neuroscience Aug 2021Synucleinopathy disorders are characterized by aggregates of α-synuclein (α-syn), which engage microglia to elicit a neuroinflammatory response. Here, we determined...
Synucleinopathy disorders are characterized by aggregates of α-synuclein (α-syn), which engage microglia to elicit a neuroinflammatory response. Here, we determined the gene expression and DNA methylation changes in microglia induced by aggregate α-syn. Transgenic murine Thy-1 promoter (mThy1)-Asyn mice overexpressing human α-syn are a model of synucleinopathy. Microglia from 3 and 13-month-old mice were used to isolate nucleic acids for methylated DNA and RNA-sequencing. α-Syn-regulated changes in gene expression and genomic methylation were determined and examined for functional enrichment followed by network analysis to further elucidate possible connections within the data. Microglial DNA isolated from our 3-month cohort had 5315 differentially methylated gene (DMG) changes, while RNA levels demonstrated a change in 119 differentially expressed genes (DEGs) between mThy1-Asyn mice and wild-type littermate controls. The 3-month DEGs and DMGs were highly associated with adhesion and migration signaling, suggesting a phenotypic transition from resting to active microglia. We observed 3742 DMGs and 3766 DEGs in 13-month mThy1-Asyn mice. These genes were often related to adhesion, migration, cell cycle, cellular metabolism, and immune response. Network analysis also showed increased cell mobility and inflammatory functions at 3 months, shifting to cell cycle, immune response, and metabolism changes at 13 months. We observed significant α-syn-induced methylation and gene expression changes in microglia. Our data suggest that α-syn overexpression initiates microglial activation leading to neuroinflammation and cellular metabolic stresses, which is associated with disease progression.
Topics: Animals; DNA Methylation; Disease Models, Animal; Gene Expression; Inflammation; Mice; Mice, Inbred C57BL; Microglia; alpha-Synuclein
PubMed: 34082066
DOI: 10.1016/j.neuroscience.2021.05.027 -
International Journal of Molecular... Apr 2023Alpha-synuclein (αS) is a small, presynaptic neuronal protein encoded by the gene. Point mutations and gene multiplication of cause rare familial forms of Parkinson's... (Review)
Review
Alpha-synuclein (αS) is a small, presynaptic neuronal protein encoded by the gene. Point mutations and gene multiplication of cause rare familial forms of Parkinson's disease (PD). Misfolded αS is cytotoxic and is a component of Lewy bodies, which are a pathological hallmark of PD. Because multiplication is sufficient to cause full-blown PD, gene dosage likely has a strong impact on pathogenesis. In sporadic PD, increased expression resulting from a minor genetic background and various environmental factors may contribute to pathogenesis in a complementary manner. With respect to genetic background, several risk loci neighboring the gene have been identified, and epigenetic alterations, such as CpG methylation and regulatory histone marks, are considered important factors. These alterations synergistically upregulate αS expression and some post-translational modifications of αS facilitate its translocation to the nucleus. Nuclear αS interacts with DNA, histones, and their modifiers to alter epigenetic status; thereby, influencing the stability of neuronal function. Epigenetic changes do not affect the gene itself but can provide an appropriate transcriptional response for neuronal survival through DNA methylation or histone modifications. As a new approach, publicly available RNA sequencing datasets from human midbrain-like organoids may be used to compare transcriptional responses through epigenetic alterations. This informatic approach combined with the vast amount of transcriptomics data will lead to the discovery of novel pathways for the development of disease-modifying therapies for PD.
Topics: Humans; alpha-Synuclein; Parkinson Disease; Gene Expression; Epigenesis, Genetic; DNA Methylation
PubMed: 37047616
DOI: 10.3390/ijms24076645 -
Protein Science : a Publication of the... Jul 2021In Parkinson's disease with dementia, up to 50% of patients develop a high number of tau-containing neurofibrillary tangles. Tau-based pathologies may thus act...
In Parkinson's disease with dementia, up to 50% of patients develop a high number of tau-containing neurofibrillary tangles. Tau-based pathologies may thus act synergistically with the α-synuclein pathology to confer a worse prognosis. A better understanding of the relationship between the two distinct pathologies is therefore required. Liquid-liquid phase separation (LLPS) of proteins has recently been shown to be important for protein aggregation involved in amyotrophic lateral sclerosis, whereas tau phase separation has been linked to Alzheimer's disease. We therefore investigated the interaction of α-synuclein with tau and its consequences on tau LLPS. We find α-synuclein to have a low propensity for both, self-coacervation and RNA-mediated LLPS at pH 7.4. However, full-length but not carboxy-terminally truncated α-synuclein efficiently partitions into tau/RNA droplets. We further demonstrate that Cdk2-phosphorylation promotes the concentration of tau into RNA-induced droplets, but at the same time decreases the amount of α-synuclein inside the droplets. NMR spectroscopy reveals that the interaction of the carboxy-terminal domain of α-synuclein with the proline-rich region P2 of tau is required for the recruitment of α-synuclein into tau droplets. The combined data suggest that the concentration of α-synuclein into tau-associated condensates can contribute to synergistic aSyn/tau pathologies.
Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Humans; Recombinant Proteins; alpha-Synuclein; tau Proteins
PubMed: 33452693
DOI: 10.1002/pro.4025 -
Molecules (Basel, Switzerland) Nov 2020Alpha-synuclein (αS) is an extensively studied protein due to its involvement in a group of neurodegenerative disorders, including Parkinson's disease, and its... (Review)
Review
Alpha-synuclein (αS) is an extensively studied protein due to its involvement in a group of neurodegenerative disorders, including Parkinson's disease, and its documented ability to undergo aberrant self-aggregation resulting in the formation of amyloid-like fibrils. In dilute solution, the protein is intrinsically disordered but can adopt multiple alternative conformations under given conditions, such as upon adsorption to nanoscale surfaces. The study of αS-nanoparticle interactions allows us to better understand the behavior of the protein and provides the basis for developing systems capable of mitigating the formation of toxic aggregates as well as for designing hybrid nanomaterials with novel functionalities for applications in various research areas. In this review, we summarize current progress on αS-nanoparticle interactions with an emphasis on the conformational plasticity of the biomolecule.
Topics: Adsorption; Amyloid; Humans; Molecular Conformation; Nanoconjugates; Nanoparticles; Protein Aggregates; alpha-Synuclein
PubMed: 33260436
DOI: 10.3390/molecules25235625 -
Movement Disorders : Official Journal... Feb 2016Immunotherapy using antibodies targeting alpha-synuclein has proven to be an effective strategy for ameliorating pathological and behavioral deficits induced by excess... (Review)
Review
Immunotherapy using antibodies targeting alpha-synuclein has proven to be an effective strategy for ameliorating pathological and behavioral deficits induced by excess pathogenic alpha-synuclein in various animal and/or cellular models. However, the process of selecting the anti-alpha-synuclein antibody with the best potential to treat synucleinopathies in humans is not trivial. Critical to this process is a better understanding of the pathological processes involved in the synucleinopathies and how antibodies are able to influence these. We will give an overview of the first proof-of-concept studies in rodent disease models and discuss challenges associated with developing antibodies against alpha-synuclein resulting from the distribution and structural characteristics of the protein. We will also provide a status on the passive immunization approaches targeting alpha-synuclein that have entered, or are expected to enter, clinical evaluation.
Topics: Animals; Disease Models, Animal; Immunization, Passive; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; alpha-Synuclein
PubMed: 26704735
DOI: 10.1002/mds.26481