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IUBMB Life Apr 2020Synucleinopathies are neurodegenerative diseases characterized by the accumulation of either neuronal/axonal or glial insoluble proteinaceous aggregates mainly composed... (Review)
Review
Synucleinopathies are neurodegenerative diseases characterized by the accumulation of either neuronal/axonal or glial insoluble proteinaceous aggregates mainly composed of α-synuclein (α-syn). Among them, the most common disorders are Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and some forms of familial parkinsonism. Both α-syn fibrils and oligomers have been found to exert toxic effects on neurons or oligodendroglial cells, can activate neuroinflammatory responses, and mediate the spreading of α-syn pathology. This poses the question of which is the most toxic α-syn species. What is worst, α-syn appears as a very peculiar protein, exerting multiple physiological functions in neurons, especially at synapses, but without acquiring a stable tertiary structure. Its conformation is particularly plastic, and the protein can exist in a natively unfolded state (mainly in solution), partially α-helical folded state (when it interacts with biological membranes), or oligomeric state (tetramers or dimers with debated functional profile). The extent of α-syn expression impinges on the resilience of neuronal cells, as multiplications of its gene locus, or overexpression, can cause neurodegeneration and onset of motor phenotype. For these reasons, one of the main challenges in the field of synucleinopathies, which still nowadays can only be managed by symptomatic therapies, has been the development of strategies aimed at reducing α-syn levels, oligomer formation, fibrillation, or cell-to-cell transmission. This review resumes the therapeutic approaches that have been proposed or are under development to counteract α-syn pathology by direct targeting of this protein and discuss their pros and cons in relation to the current state-of-the-art α-syn biology.
Topics: Animals; Genetic Therapy; Humans; Immunotherapy; Intermediate Filament Proteins; Molecular Targeted Therapy; Multiple System Atrophy; Parkinson Disease; Synapses; alpha-Synuclein
PubMed: 31693290
DOI: 10.1002/iub.2194 -
Journal of Peptide Science : An... Apr 2022Protein misfolding and aggregation play a vital role in several human diseases such as Parkinson's, Alzheimer's, and prion diseases. The development of nanoparticles...
Protein misfolding and aggregation play a vital role in several human diseases such as Parkinson's, Alzheimer's, and prion diseases. The development of nanoparticles that modulate aggregation could be potential drug candidates for these neurodegenerative disorders. Parkinson's disease pathogenesis is closely associated with the accumulation of α-synuclein oligomers and fibrils in the substantia nigra of the brain. This report discusses the interactions of novel tryptophan-cardanol nanoparticles with α-synuclein protein monomers and fibrils. These nanoparticles could effectively disrupt α-synuclein fibrils and inhibit fibril formation at low concentrations such as 5 μM. The tryptophan-cardanol nanoparticles inhibit fibril formation from unstructured protein resulting in spherical nanostructures. These nanoparticles could also disassemble amyloid fibrils; the complete disappearance of fibrils was evident after 48 h of incubation with tryptophan-cardanol. The transmission electron microscopy (TEM) micrographs after the incubation did not show any remnants of the peptide aggregates or oligomers. The thioflavin T fluorescence after the disassembly was diminished compared with that of fibrils also supports the inhibitory effect of the nanoparticles. Also, these nanoparticles did not reduce the viability of the SH-SY5Y cells. These findings suggest that the tryptophan-cardanol nanoparticles showed sufficiently high inhibitory activity and may have therapeutic potential for synucleinopathies.
Topics: Amyloid; Nanoparticles; Phenols; Tryptophan; alpha-Synuclein
PubMed: 34651357
DOI: 10.1002/psc.3374 -
Structures of tau and α-synuclein filaments from brains of patients with neurodegenerative diseases.Neurochemistry International Sep 2022Intracellular accumulations and aggregates of abnormal protein, consisting of amyloid-like fibrils, are common neuropathological features of many neurodegenerative... (Review)
Review
Intracellular accumulations and aggregates of abnormal protein, consisting of amyloid-like fibrils, are common neuropathological features of many neurodegenerative diseases. The distributions and spreading of these pathological proteins are closely correlated with clinical symptoms and progression. Recent evidence supports the idea that template-mediated amplification of amyloid-like fibrils and intracellular propagation of fibril seeds are the main mechanisms by which pathological features spread along the neural circuits in the brain. Here, we review recent developments in the structural analysis of amyloid-like fibrils from brains of patients with various types of tauopathy and α-synucleinopathy, focusing on cryo-electron microscopy and mass analysis, and we discuss their relevance to the mechanisms of template-mediated amplification and intracellular propagation.
Topics: Amyloid; Brain; Cryoelectron Microscopy; Humans; Neurodegenerative Diseases; Tauopathies; alpha-Synuclein; tau Proteins
PubMed: 35659527
DOI: 10.1016/j.neuint.2022.105362 -
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 -
Biomolecules Apr 2023The Lewy bodies and Lewy neurites are key pathological hallmarks of Parkinson's disease (PD). Single-point mutations associated with familial PD cause α-synuclein...
The Lewy bodies and Lewy neurites are key pathological hallmarks of Parkinson's disease (PD). Single-point mutations associated with familial PD cause α-synuclein (α-Syn) aggregation, leading to the formation of Lewy bodies and Lewy neurites. Recent studies suggest α-Syn nucleates through liquid-liquid phase separation (LLPS) to form amyloid aggregates in a condensate pathway. How PD-associated mutations affect α-Syn LLPS and its correlation with amyloid aggregation remains incompletely understood. Here, we examined the effects of five mutations identified in PD, A30P, E46K, H50Q, A53T, and A53E, on the phase separation of α-Syn. All other α-Syn mutants behave LLPS similarly to wild-type (WT) α-Syn, except that the E46K mutation substantially promotes the formation of α-Syn condensates. The mutant α-Syn droplets fuse to WT α-Syn droplets and recruit α-Syn monomers into their droplets. Our studies showed that α-Syn A30P, E46K, H50Q, and A53T mutations accelerated the formation of amyloid aggregates in the condensates. In contrast, the α-Syn A53E mutant retarded the aggregation during the liquid-to-solid phase transition. Finally, we observed that WT and mutant α-Syn formed condensates in the cells, whereas the E46K mutation apparently promoted the formation of condensates. These findings reveal that familial PD-associated mutations have divergent effects on α-Syn LLPS and amyloid aggregation in the phase-separated condensates, providing new insights into the pathogenesis of PD-associated α-Syn mutations.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Mutation; Lewy Bodies; Point Mutation; Amyloid; Amyloidogenic Proteins
PubMed: 37238596
DOI: 10.3390/biom13050726 -
Molecular Neurobiology Aug 2023Parkinson's disease (PD), the second-most prevalent neurodegenerative disorder, is characterized by the aberrant deposition of α-synuclein (α-Syn) aggregation in...
Parkinson's disease (PD), the second-most prevalent neurodegenerative disorder, is characterized by the aberrant deposition of α-synuclein (α-Syn) aggregation in neurons. Recent reports have shown that retinoic acid (RA) ameliorates motor deficits. However, the underlying molecular mechanisms remain unclear. In this article, we investigated the effects of RA on cellular and animal models of PD. We found that RA is beneficial for neuronal survival in PD-associated models. In α-Syn preformed fibrils-treated mice, RA administration relieved the formation of intracellular inclusions, dopaminergic neuronal loss, and behavioral deficits. α-Syn preformed fibrils-treated SH-SY5Y cells manifested decreased cell viability, apoptosis, α-Syn aggregation, and autophagy defects. All these negative phenomena were alleviated by RA. More importantly, RA could inhibit the neurotoxicity via inhibiting α-Syn preformed fibrils-induced STAT1-PARP1 signaling, which could also be antagonized by IFN-γ. In conclusion, RA could hinder α-Syn preformed fibrils-induced toxicity by inhibiting STAT1-PARP1 signaling. Thus, we present new insight into RA in PD management.
Topics: Mice; Humans; Animals; alpha-Synuclein; Tretinoin; Neuroblastoma; Parkinson Disease; Neurons; STAT1 Transcription Factor; Poly (ADP-Ribose) Polymerase-1
PubMed: 37171576
DOI: 10.1007/s12035-023-03376-x -
Nuclear Medicine and Biology 2022This review outlines small molecule radiotracers developed for positron emission tomography (PET) imaging of proteinopathies, neurodegenerative diseases characterised by... (Review)
Review
This review outlines small molecule radiotracers developed for positron emission tomography (PET) imaging of proteinopathies, neurodegenerative diseases characterised by accumulation of malformed proteins, over the last two decades with the focus on radioligands that have progressed to clinical studies. Introduction provides a short summary of proteinopathy targets used for PET imaging, including vastly studied proteins Aβ and tau and emerging α-synuclein. In the main section, clinically relevant Aβ and tau radioligand classes and their properties are discussed, including an overview of lead compounds and radioligand candidates studied as α-synuclein imaging agents in the early discovery and preclinical development phase. Lastly, the specific challenges and future directions in proteinopathy radioligand development are summarized.
Topics: Humans; alpha-Synuclein; Alzheimer Disease; Brain; Positron-Emission Tomography; Proteostasis Deficiencies; tau Proteins
PubMed: 35487833
DOI: 10.1016/j.nucmedbio.2022.04.001 -
Frontiers in Bioscience (Landmark... Oct 2023Dopaminergic neurons are constantly threatened by the thin boundaries between functional α-synuclein (AS) structural disorder and pathogenic aggregation, and between... (Review)
Review
Dopaminergic neurons are constantly threatened by the thin boundaries between functional α-synuclein (AS) structural disorder and pathogenic aggregation, and between dopamine (DA) neurotransmitter activity and accumulation of cytotoxic by-products. The possibilities of developing drugs for Parkinson's disease (PD) depend on our understanding of the molecular mechanisms that cause or accompany the pathological structural changes in AS. This review focuses on the three interconnected aspects of AS conformational transitions, its aggregation pathways and ligand binding. Specifically, the interactions of AS with DA, DA metabolites, DA analogs and DA agonists are considered. Recent advances in the field are discussed with reference to the structural properties of AS and the methodologies employed. Although several issues are still object of debate, salient structural features of the protein, the aggregates and the ligands can be identified, in the hope of fueling experimental and computational approaches to the discovery of novel disease-modifying agents.
Topics: Humans; alpha-Synuclein; Dopamine; Parkinson Disease; Dopaminergic Neurons; Molecular Conformation
PubMed: 37919088
DOI: 10.31083/j.fbl2810266 -
International Journal of Molecular... Aug 2022The gene encodes a cytosolic protein that binds to the signaling cascade component neuronal nitric oxide synthase (nNOS). It is associated with many different...
The gene encodes a cytosolic protein that binds to the signaling cascade component neuronal nitric oxide synthase (nNOS). It is associated with many different disorders, such as schizophrenia, post-traumatic stress disorder, autism, cardiovascular disorders, and breast cancer. The NOS1AP (also known as CAPON) protein mediates signaling within a complex which includes the NMDA receptor, PSD-95, and nNOS. This adapter protein is involved in neuronal nitric oxide (NO) synthesis regulation via its association with nNOS (NOS1). Our bioinformatics analysis revealed NOS1AP as an aggregation-prone protein, interacting with α-synuclein. Further investigation showed that NOS1AP forms detergent-resistant non-amyloid aggregates when overproduced. Overexpression of was found in rat models for nervous system injury as well as in schizophrenia patients. Thus, we can assume for the first time that the molecular mechanisms underlying these disorders include misfolding and aggregation of NOS1AP. We show that NOS1AP interacts with α-synuclein, allowing us to suggest that this protein may be implicated in the development of synucleinopathies and that its aggregation may explain the relationship between Parkinson's disease and schizophrenia.
Topics: Adaptor Proteins, Signal Transducing; Animals; Neurons; Nitric Oxide Synthase Type I; Rats; Saccharomyces cerevisiae; Signal Transduction; Synucleinopathies; alpha-Synuclein
PubMed: 36012368
DOI: 10.3390/ijms23169102