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Science Advances Aug 2023α-Synuclein (α-Syn) aggregation into fibrils with prion-like features is intimately associated with Lewy pathology and various synucleinopathies. Emerging studies...
α-Synuclein (α-Syn) aggregation into fibrils with prion-like features is intimately associated with Lewy pathology and various synucleinopathies. Emerging studies suggest that α-Syn could form liquid condensates through phase separation. The role of these condensates in aggregation and disease remains elusive and the interplay between α-Syn fibrils and α-Syn condensates remains unexplored, possibly due to difficulties in triggering the formation of α-Syn condensates in cells. To address this gap, we developed an assay allowing the controlled assembly/disassembly of α-Syn condensates in cells and studied them upon exposure to preformed α-Syn fibrillar polymorphs. Fibrils triggered the evolution of liquid α-Syn condensates into solid-like structures displaying growing needle-like extensions and exhibiting pathological amyloid hallmarks. No such changes were elicited on α-Syn that did not undergo phase separation. We, therefore, propose a model where α-Syn within condensates fuels exogenous fibrillar seeds growth, thus speeding up the prion-like propagation of pathogenic aggregates.
Topics: alpha-Synuclein; Amyloid; Prions
PubMed: 37585526
DOI: 10.1126/sciadv.adg5663 -
Nature Communications Nov 2023Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson's disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD....
Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson's disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD. This α-synucleinopathy leads to mitochondrial dysfunction, which may drive dopaminergic neurodegeneration. PARKIN and PINK1, mutated in autosomal recessive PD, regulate the preferential autophagic clearance of dysfunctional mitochondria ("mitophagy") by inducing ubiquitylation of mitochondrial proteins, a process counteracted by deubiquitylation via USP30. Here we show that loss of USP30 in Usp30 knockout mice protects against behavioral deficits and leads to increased mitophagy, decreased phospho-S129 αSyn, and attenuation of SN dopaminergic neuronal loss induced by αSyn. These observations were recapitulated with a potent, selective, brain-penetrant USP30 inhibitor, MTX115325, with good drug-like properties. These data strongly support further study of USP30 inhibition as a potential disease-modifying therapy for PD.
Topics: Animals; Mice; alpha-Synuclein; Dopaminergic Neurons; Mice, Knockout; Mitochondria; Parkinson Disease; Ubiquitin-Protein Ligases; Ubiquitination; Thiolester Hydrolases
PubMed: 37957154
DOI: 10.1038/s41467-023-42876-1 -
Trends in Neurosciences Mar 2024Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies (LBs). The main proteinaceous component of LBs is aggregated α-synuclein (α-syn). However, the mechanisms underlying α-syn aggregation are not yet fully understood. Converging lines of evidence indicate that, under certain pathological conditions, various proteins can interact with α-syn and regulate its aggregation. Understanding these protein-protein interactions is crucial for unraveling the molecular mechanisms contributing to PD pathogenesis. In this review we provide an overview of the current knowledge on protein-protein interactions that regulate α-syn aggregation. Additionally, we briefly summarize the methods used to investigate the influence of protein-protein interactions on α-syn aggregation and propagation.
Topics: Humans; alpha-Synuclein; Dopaminergic Neurons; Neurodegenerative Diseases; Parkinson Disease
PubMed: 38355325
DOI: 10.1016/j.tins.2024.01.002 -
The Journal of Biological Chemistry Sep 2023α-Synuclein and family members β- and γ-synuclein are presynaptic proteins that sense and generate membrane curvature, properties important for synaptic vesicle (SV)...
α-Synuclein and family members β- and γ-synuclein are presynaptic proteins that sense and generate membrane curvature, properties important for synaptic vesicle (SV) cycling. αβγ-synuclein triple knockout neurons exhibit SV endocytosis deficits. Here, we investigated if α-synuclein affects clathrin assembly in vitro. Visualizing clathrin assembly on membranes using a lipid monolayer system revealed that α-synuclein increases clathrin lattices size and curvature. On cell membranes, we observe that α-synuclein is colocalized with clathrin and its adapter AP180 in a concentric ring pattern. Clathrin puncta that contain both α-synuclein and AP180 were significantly larger than clathrin puncta containing either protein alone. We determined that this effect occurs in part through colocalization of α-synuclein with the phospholipid PI(4,5)P2 in the membrane. Immuno-electron microscopy (EM) of synaptosomes uncovered that α-synuclein relocalizes from SVs to the presynaptic membrane upon stimulation, positioning α-synuclein to function on presynaptic membranes during or after stimulation. Additionally, we show that deletion of synucleins impacts brain-derived clathrin-coated vesicle size. Thus, α-synuclein affects the size and curvature of clathrin structures on membranes and functions as an endocytic accessory protein.
Topics: alpha-Synuclein; Cell Membrane; Clathrin; Endocytosis; Microscopy, Immunoelectron; Monomeric Clathrin Assembly Proteins; Neurons; Presynaptic Terminals; Synaptosomes; Protein Transport; In Vitro Techniques; Phosphatidylinositol 4,5-Diphosphate; Brain; Clathrin-Coated Vesicles
PubMed: 37516240
DOI: 10.1016/j.jbc.2023.105091 -
Proceedings of the National Academy of... Oct 2023α-synuclein (α-Syn) is a presynaptic protein that is involved in Parkinson's and other neurodegenerative diseases and binds to negatively charged phospholipids....
α-synuclein (α-Syn) is a presynaptic protein that is involved in Parkinson's and other neurodegenerative diseases and binds to negatively charged phospholipids. Previously, we reported that α-Syn clusters synthetic proteoliposomes that mimic synaptic vesicles. This vesicle-clustering activity depends on a specific interaction of α-Syn with anionic phospholipids. Here, we report that α-Syn surprisingly also interacts with the neutral phospholipid lysophosphatidylcholine (lysoPC). Even in the absence of anionic lipids, lysoPC facilitates α-Syn-induced vesicle clustering but has no effect on Ca-triggered fusion in a single vesicle-vesicle fusion assay. The A30P mutant of α-Syn that causes familial Parkinson disease has a reduced affinity to lysoPC and does not induce vesicle clustering. Taken together, the α-Syn-lysoPC interaction may play a role in α-Syn function.
Topics: Humans; alpha-Synuclein; Synaptic Vesicles; Lysophosphatidylcholines; Parkinson Disease; Phospholipids
PubMed: 37883437
DOI: 10.1073/pnas.2310174120 -
JCI Insight Nov 2023Cerebrotendinous xanthomatosis (CTX), an autosomal recessive disorder characterized by high levels of cholestanol in the blood and accumulation of cholestanol in...
Cerebrotendinous xanthomatosis (CTX), an autosomal recessive disorder characterized by high levels of cholestanol in the blood and accumulation of cholestanol in multiple tissues, especially the brain, often presents in parkinsonism. However, it remains unknown whether cholestanol plays a role in the pathogenesis of sporadic Parkinson's disease (PD). Here, we show that the levels of serum cholestanol in patients with sporadic PD are higher than those in control participants. Cholestanol activates the protease asparagine endopeptidase (AEP) and induces the fragmentation of α-synuclein (α-syn) and facilitates its aggregation. Furthermore, cholestanol promotes the spreading of α-syn pathology in a mouse model induced by intrastriatal injection of α-syn fibrils. KO of AEP or administration of an AEP inhibitor ameliorates α-syn pathology, degeneration of the nigrostriatal dopaminergic pathway, and PD-like motor symptoms. These results not only indicate that cholestanol contributes to the aggregation and spreading of α-syn by activating AEP but also reveal an opportunity for treating PD with AEP inhibitors.
Topics: Mice; Animals; Humans; alpha-Synuclein; Parkinson Disease; Cysteine Endopeptidases; Cholestanols
PubMed: 37937646
DOI: 10.1172/jci.insight.165841 -
Biophysical Chemistry Dec 2023Parkinson's disease (PD) is an aging-associated neurodegenerative disorder with the hallmark of abnormal aggregates of alpha-synuclein (α-syn) in Lewy bodies (LBs) and... (Review)
Review
Parkinson's disease (PD) is an aging-associated neurodegenerative disorder with the hallmark of abnormal aggregates of alpha-synuclein (α-syn) in Lewy bodies (LBs) and Lewy neurites (LNs). Currently, pathogenic α-syn and mitochondrial dysfunction have been considered as prominent roles that give impetus to the PD onset. This review describes the α-syn pathology and mitochondrial alterations in PD, and focuses on how α-syn interacts with multiple aspects of mitochondrial homeostasis in the pathogenesis of PD.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Lewy Bodies; Neurodegenerative Diseases; Mitochondria
PubMed: 37839353
DOI: 10.1016/j.bpc.2023.107122 -
Biomedicine & Pharmacotherapy =... Dec 2023α-Synuclein is a member of a protein of synucleins, which is a presynaptic neuron protein. It is usually highly expressed in the brain and participates in the formation... (Review)
Review
α-Synuclein is a member of a protein of synucleins, which is a presynaptic neuron protein. It is usually highly expressed in the brain and participates in the formation and transmission of nerve synapses. It has been reported that abnormal aggregation of α-Syn can induce the activation of NLRP3 inflammasome in microglia, increase the production of IL-1β, and aggravate neuroinflammation. Therefore, it is recognized as one of the important factors leading to neuroinflammation in Parkinson's disease. In this paper, we aimed to explore the influence of post-translational modification of α-Syn on its pathological aggregation and summarize various pathways that activate NLRP3 triggered by α-Syn and targeted therapeutic strategies, which provided new insights for further exploring the origin and targeted therapy of Parkinson's disease.
Topics: Humans; alpha-Synuclein; Inflammasomes; Microglia; Neuroinflammatory Diseases; NLR Family, Pyrin Domain-Containing 3 Protein; Parkinson Disease
PubMed: 37852103
DOI: 10.1016/j.biopha.2023.115735 -
Gut Microbes Dec 2023Alpha-synuclein (α-syn) pathology is the hallmark of Parkinson's disease (PD). The leucine-rich repeat kinase 2 () gene is a major-effect risk gene for sporadic PD...
Alpha-synuclein (α-syn) pathology is the hallmark of Parkinson's disease (PD). The leucine-rich repeat kinase 2 () gene is a major-effect risk gene for sporadic PD (sPD). However, what environmental factors may trigger the formation of α-syn pathology in carriers of risk variants are still unknown. Here, we report that a markedly increased abundance of (. ) in the intestinal microbiota was detected in risk variant(R1628P or G2385R) carriers with sPD compared with carriers without sPD. Animal experiments showed that . administration triggered pathological α-syn accumulation in the colon and spread to the brain via the gut-brain axis in R1628P mice, due to the co-occurrence of variant-induced inhibition of α-syn autophagic degradation and increased phosphorylation of α-syn caused by curli in . -derived extracellular vesicles. Fecal microbiota transplantation (FMT) effectively ameliorated motor deficits and α-syn pathology in R1628P mice. Our findings elaborate on the mechanism that triggers α-syn pathology in R1628P mice, and highlight a novel gene-environment interaction pattern in risk variants. Even more importantly, the findings reveal the interplay between the specific risk gene and the matched environmental factors triggers the initiation of α-syn pathology in sPD.
Topics: Mice; Animals; Parkinson Disease; Mice, Transgenic; alpha-Synuclein; Escherichia coli; Gastrointestinal Microbiome
PubMed: 38010914
DOI: 10.1080/19490976.2023.2276296 -
International Journal of Molecular... Dec 2023Parkinson's disease (PD) is a complex neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the widespread... (Review)
Review
Parkinson's disease (PD) is a complex neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the widespread accumulation of alpha-synuclein (αSyn) protein aggregates. αSyn aggregation disrupts critical cellular processes, including synaptic function, mitochondrial integrity, and proteostasis, which culminate in neuronal cell death. Importantly, αSyn pathology extends beyond neurons-it also encompasses spreading throughout the neuronal environment and internalization by microglia and astrocytes. Once internalized, glia can act as neuroprotective scavengers, which limit the spread of αSyn. However, they can also become reactive, thereby contributing to neuroinflammation and the progression of PD. Recent advances in αSyn research have enabled the molecular diagnosis of PD and accelerated the development of targeted therapies. Nevertheless, despite more than two decades of research, the cellular function, aggregation mechanisms, and induction of cellular damage by αSyn remain incompletely understood. Unraveling the interplay between αSyn, neurons, and glia may provide insights into disease initiation and progression, which may bring us closer to exploring new effective therapeutic strategies. Herein, we provide an overview of recent studies emphasizing the multifaceted nature of αSyn and its impact on both neuron and glial cell damage.
Topics: alpha-Synuclein; Dopaminergic Neurons; Neurodegenerative Diseases; Neuroglia; Parkinson Disease
PubMed: 38203531
DOI: 10.3390/ijms25010360