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Molecular Neurodegeneration Nov 2023
Topics: Phosphorylation; alpha-Synuclein; Protein Serine-Threonine Kinases
PubMed: 37953316
DOI: 10.1186/s13024-023-00680-x -
Journal of Molecular Biology Jan 2023
Topics: Membranes; Synapses; SNARE Proteins; alpha-Synuclein
PubMed: 36481178
DOI: 10.1016/j.jmb.2022.167905 -
Biomolecules Mar 2022In 1957, Lionel Penrose built the first man-made self-replicating mechanical device and illustrated its function in a series of machine prototypes, prefiguring our... (Review)
Review
In 1957, Lionel Penrose built the first man-made self-replicating mechanical device and illustrated its function in a series of machine prototypes, prefiguring our current view of the genesis and the proliferation of amyloid fibrils. He invented and demonstrated, with the help of his son Roger, the concepts that decades later, would become the fundamentals of prion and prion-like neurobiology: nucleation, seeding and conformational templating of monomers, linear polymer elongation, fragmentation, and spread. He published his premonitory discovery in a movie he publicly presented at only two conferences in 1958, a movie we thus reproduce here. By making a 30-year-jump in the early 90's, we evoke the studies performed by Peter Lansbury and his group in which α-Synuclein (α-Syn) was for the first time (i) compared to a prion; (ii) shown to contain a fibrillization-prone domain capable of seeding its own assembly into fibrils; (iii) identified as an intrinsically disordered protein (IDP), and which, in the early 2000s, (iv) was described by one of us as a protein chameleon. We use these temporally distant breakthroughs to propose that the combination of the chameleon nature of α-Syn with the rigid gear of the Penrose machine is sufficient to account for a phenomenon that is of current interest: the emergence and the spread of a variety of α-Syn fibril strains in α-Synucleinopathies.
Topics: Amyloid; Humans; Intrinsically Disordered Proteins; Prions; Synucleinopathies; alpha-Synuclein
PubMed: 35454083
DOI: 10.3390/biom12040494 -
Chemphyschem : a European Journal of... Mar 2021Parkinson's disease is a neurodegenerative disorder involving a functional protein, α-synuclein, whose primary function is related to vesicle trafficking. However,...
Parkinson's disease is a neurodegenerative disorder involving a functional protein, α-synuclein, whose primary function is related to vesicle trafficking. However, α-synuclein is prone to form aggregates, and these inclusions, known as Lewy bodies, are the hallmark of Parkinson's disease. α-synuclein can alter its conformation and acquire aggregating capacity, forming aggregates containing β-sheets. This protein's pathogenic importance is based on its ability to form oligomers that impair synaptic transmission and neuronal function by increasing membrane permeability and altering homeostasis, generating a deleterious effect over cells. First, we establish that oligomers interfere with the mechanical properties of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membrane, as demonstrated by nanoindentation curves. In contrast, nanoindentation revealed that the α-synuclein monomer's presence leads to a much more resistant lipid bilayer. Moreover, the oligomers' interaction with cell membranes can promote lactate dehydrogenase (LDH) release, suggesting the activation of cytotoxic events.
Topics: Animals; Cell Line, Tumor; Cell Membrane; Hydrophobic and Hydrophilic Interactions; L-Lactate Dehydrogenase; Lipid Bilayers; Mice; Phosphatidylcholines; Protein Aggregates; Protein Multimerization; alpha-Synuclein
PubMed: 33482036
DOI: 10.1002/cphc.202000831 -
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) Jan 2020The object of our analysis is the structure of alpha-synuclein (ASyn), which, under in vivo conditions, associates with presynaptic vesicles. Misfolding of ASyn is known...
The object of our analysis is the structure of alpha-synuclein (ASyn), which, under in vivo conditions, associates with presynaptic vesicles. Misfolding of ASyn is known to be implicated in Parkinson's disease. The availability of structural information for both the micelle-bound and amyloid form of ASyn enables us to speculate on the specific mechanism of amyloid transformation. This analysis is all the more interesting given the fact that-Unlike in Aβ(1-42) amyloids-only the central fragment (30-100) of ASyn has a fibrillar structure, whereas, its N- and C-terminal fragments (1-30 and 100-140, respectively) are described as random coils. Our work addresses the following question: Can the ASyn chain-as well as the aforementioned individual fragments-adopt globular conformations? In order to provide an answer, we subjected the corresponding sequences to simulations carried out using Robetta and I-Tasser, both of which are regarded as accurate protein structure predictors. In addition, we also applied the fuzzy oil drop (FOD) model, which, in addition to optimizing the protein's internal free energy, acknowledges the presence of an external force field contributed by the aqueous solvent. This field directs hydrophobic residues to congregate near the center of the protein body while exposing hydrophilic residues on its surface. Comparative analysis of the obtained models suggests that fragments which do not participate in forming the amyloid fibril (i.e., 1-30 and 100-140) can indeed attain globular conformations. We also explain the influence of mutations observed in vivo upon the susceptibility of ASyn to undergo amyloid transformation. In particular, the 30-100 fragment (which adopts a fibrillar structure in PDB) is not predicted to produce a centralized hydrophobic core by any of the applied toolkits (Robetta, I-Tasser, and FOD). This means that in order to minimize the entropically disadvantageous contact between hydrophobic residues and the polar solvent, ASyn adopts the form of a ribbonlike micelle (rather than a spherical one). In other words, the ribbonlike micelle represents a synergy between the conformational preferences of the protein chain and the influence of its environment.
Topics: Amyloid; Humans; Hydrophobic and Hydrophilic Interactions; Models, Molecular; Mutation; Peptide Fragments; Protein Conformation; alpha-Synuclein
PubMed: 32019169
DOI: 10.3390/molecules25030600 -
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 -
Biophysical Chemistry Jun 2023Human alpha-synuclein (αS) is associated with the occurrence of Parkinson's disease. In the past decade, six autosomally dominant mutations have been identified in αS...
Human alpha-synuclein (αS) is associated with the occurrence of Parkinson's disease. In the past decade, six autosomally dominant mutations have been identified in αS (SNCA) gene that translate into A30P, E46K, H50Q, G51D, A53E, and A53T mutations in the protein. These mutations alter the electrostatics and hydrophobicity of a cardinal region of the protein. A comprehensive comparison of interfacial properties of these Parkinsonian αS variants is crucial to understand their membrane dynamics. Here, we investigated the interfacial activity of these αS variants at air-aqueous interface. All the αS variants were found to possess comparable surface activity of ∼20-22 mN/m. Compression/expansion isotherms reveal a very distinct behaviour of the A30P variant compared to others. The Blodgett-deposited films were analysed using CD and LD spectroscopy as well as the atomic force microscopy. All the variants adopted predominantly α-helical conformation in these films. Atomic force microscopy of the Langmuir-Blodgett films revealed self-assembly at the interface. The lipid-penetration activity was also investigated using zwitterionic and negatively charged lipid monolayers.
Topics: Humans; alpha-Synuclein; Parkinson Disease; Mutation; Gene Expression; Lipids
PubMed: 37019052
DOI: 10.1016/j.bpc.2023.107006 -
Biophysical Chemistry Feb 2022Cytoplasmic deposition of aberrantly misfolded α-synuclein (α-Syn) is a common feature of synucleinopathies, including Parkinson's disease (PD). However, the precise... (Review)
Review
Cytoplasmic deposition of aberrantly misfolded α-synuclein (α-Syn) is a common feature of synucleinopathies, including Parkinson's disease (PD). However, the precise pathogenic mechanism of α-Syn in synucleinopathies remains elusive. Emerging evidence has suggested that α-Syn may contribute to PD pathogenesis in several ways; wherein the contribution of fibrillar species, for exerting toxicity and disease transmission, cannot be neglected. Further, the oligomeric species could be the most plausible neurotoxic species causing neuronal cell death. However, understanding the structural and molecular insights of these oligomers are very challenging due to the heterogeneity and transient nature of the species. In this review, we discuss the recent advancements in understanding the formation and role of α-Syn oligomers in PD pathogenesis. We also summarize the different types of α-Syn oligomeric species and potential mechanisms to exert neurotoxicity. Finally, we address the possible ways to target α-Syn as a promising approach against PD and the possible future directions.
Topics: Humans; Parkinson Disease; Synucleinopathies; alpha-Synuclein
PubMed: 34923391
DOI: 10.1016/j.bpc.2021.106736