Potential treatment of Parkinson’s disease using new-generation carbon nanotubes: a biomolecular in silico study

Nanomedicine ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. 189-204
Author(s):  
Ehsan Alimohammadi ◽  
Arash Nikzad ◽  
Mohammad Khedri ◽  
Milad Rezaian ◽  
Ahmad Miri Jahromi ◽  
...  
Keyword(s):  
Carbon Nanotubes ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Inhibitory Effect ◽  
Strong Interactions ◽  
Amyloid Formation ◽  
Potential Treatment ◽  
Phosphorus Doped

Background: One of the underlying mechanisms of Parkinson’s disease is the aggregation of α-synuclein proteins, including amyloids and Lewy bodies in the brain. Aim: To study the inhibitory effect of doped carbon nanotubes (CNTs) on amyloid aggregation. Materials & methods: Molecular dynamics tools were utilized to simulate the influence of CNTs doped with phosphorus, nitrogen and bromine and nitrogen on the formation of α-synuclein amyloid. Results: The CNTs exhibited strong interactions with α-synuclein, with phosphorus-doped CNTs having the most substantial interactions. Conclusion: Doped-CNTs, especially phosphorus-doped carbon nanotube could effectively prevent α-synuclein amyloid formation, thus, it could be considered as a potential treatment for Parkinson’s disease. However, further in vitro and clinical investigations are required.

scholarly journals Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies

2020 ◽  
Author(s):  
Maarten C. Hardenberg ◽  
Tessa Sinnige ◽  
Sam Casford ◽  
Samuel Dada ◽  
Chetan Poudel ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Amyloid Fibrils ◽  
Liquid Droplet ◽  
Large Body ◽  
Lewy Bodies ◽  
Amyloid Formation ◽  
C Elegans

AbstractMisfolded α-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson’s disease. A large body of evidence shows that α-synuclein can self-assemble into amyloid fibrils, but the relationship between amyloid formation and Lewy body formation still remains unclear. Here we show, both in vitro and in a C. elegans model of Parkinson’s disease, that α-synuclein undergoes liquid-liquid phase separation by forming a liquid droplet state, which converts into an amyloid-rich hydrogel. This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro. Taken together, these results suggest that the formation of Lewy bodies is linked to the arrested maturation of α-synuclein condensates in the presence of lipids and other cellular components.

scholarly journals Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies

2021 ◽  
Author(s):  
Maarten C Hardenberg ◽  
Tessa Sinnige ◽  
Sam Casford ◽  
Samuel Dada ◽  
Chetan Poudel ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Self Assembly ◽  
Lewy Body ◽  
Amyloid Fibrils ◽  
Liquid Droplet ◽  
Large Body ◽  
Lewy Bodies ◽  
Cellular Components

Abstract Misfolded α-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson’s disease. A large body of evidence shows that α-synuclein can aggregate into amyloid fibrils, but the relationship between α-synuclein self-assembly and Lewy body formation remains unclear. Here we show, both in vitro and in a Caenorhabditis elegans model of Parkinson’s disease, that α-synuclein undergoes liquid‒liquid phase separation by forming a liquid droplet state, which converts into an amyloid-rich hydrogel with Lewy-body-like properties. This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro. Taken together, these results suggest that the formation of Lewy bodies may be linked to the arrested maturation of α-synuclein condensates in the presence of lipids and other cellular components.

scholarly journals Structures of α-synuclein filaments from multiple system atrophy

2020 ◽  
Author(s):  
Manuel Schweighauser ◽  
Yang Shi ◽  
Airi Tarutani ◽  
Fuyuki Kametani ◽  
Alexey G. Murzin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Human Brain ◽  
Multiple System Atrophy ◽  
Recombinant Proteins ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Two Dimensional ◽  
Filamentous Inclusions

Synucleinopathies are human neurodegenerative diseases that include multiple system atrophy (MSA), Parkinson’s disease, Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) (1). Existing treatments are at best symptomatic. These diseases are characterised by the presence in brain cells of filamentous inclusions of α-synuclein, the formation of which is believed to cause disease (2, 3). However, the structures of α-synuclein filaments from human brain are not known. Here we show, using electron cryo-microscopy, that α-synuclein inclusions from MSA are made of two types of filaments, each of which consists of two different protofilaments. Non-proteinaceous molecules are present at the protofilament interfaces. By two-dimensional class averaging, we show that α-synuclein filaments from the brains of patients with MSA and DLB are different, suggesting that distinct conformers (or strains) characterise synucleinopathies. As was the case of tau assemblies (4–9), the structures of α-synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, with implications for understanding the mechanisms of aggregate propagation and neurodegeneration in human brain. These findings have diagnostic and potential therapeutic relevance, especially in view of the unmet clinical need to be able to image filamentous α-synuclein inclusions in human brain.

scholarly journals The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

2016 ◽  
Vol 113 (32) ◽  
pp. E4708-E4715 ◽  
Author(s):  
Timothy S. Jarvela ◽  
Hoa A. Lam ◽  
Michael Helwig ◽  
Nikolai Lorenzen ◽  
Daniel E. Otzen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disease ◽  
Primary Cultures ◽  
Lewy Bodies ◽  
Vitro Assay ◽  
Amino Terminal ◽  
Neuroprotective Function ◽  
Fluid Biomarker

Emerging evidence strongly suggests that chaperone proteins are cytoprotective in neurodegenerative proteinopathies involving protein aggregation; for example, in the accumulation of aggregated α-synuclein into the Lewy bodies present in Parkinson’s disease. Of the various chaperones known to be associated with neurodegenerative disease, the small secretory chaperone known as proSAAS (named after four residues in the amino terminal region) has many attractive properties. We show here that proSAAS, widely expressed in neurons throughout the brain, is associated with aggregated synuclein deposits in the substantia nigra of patients with Parkinson’s disease. Recombinant proSAAS potently inhibits the fibrillation of α-synuclein in an in vitro assay; residues 158–180, containing a largely conserved element, are critical to this bioactivity. ProSAAS also exhibits a neuroprotective function; proSAAS-encoding lentivirus blocks α-synuclein-induced cytotoxicity in primary cultures of nigral dopaminergic neurons, and recombinant proSAAS blocks α-synuclein–induced cytotoxicity in SH-SY5Y cells. Four independent proteomics studies have previously identified proSAAS as a potential cerebrospinal fluid biomarker in various neurodegenerative diseases. Coupled with prior work showing that proSAAS blocks β-amyloid aggregation into fibrils, this study supports the idea that neuronal proSAAS plays an important role in proteostatic processes. ProSAAS thus represents a possible therapeutic target in neurodegenerative disease.

scholarly journals Parkinson’s disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein

2019 ◽  
Vol 116 (36) ◽  
pp. 17963-17969 ◽  
Author(s):  
Katsuya Araki ◽  
Naoto Yagi ◽  
Koki Aoyama ◽  
Chi-Jing Choong ◽  
Hideki Hayakawa ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Amyloid Fibrils ◽  
Lewy Bodies ◽  
X Ray Diffraction ◽  
Thin Sections ◽  
X Ray ◽  
Β Sheet ◽  
The Brain

Many neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates in the brain. In Parkinson’s disease (PD), α-synuclein (α-syn) forms such aggregates called Lewy bodies (LBs). Recently, it has been reported that aggregates of α-syn with a cross-β structure are capable of propagating within the brain in a prionlike manner. However, the presence of cross-β sheet-rich aggregates in LBs has not been experimentally demonstrated so far. Here, we examined LBs in thin sections of autopsy brains of patients with PD using microbeam X-ray diffraction (XRD) and found that some of them gave a diffraction pattern typical of a cross-β structure. This result confirms that LBs in the brain of PD patients contain amyloid fibrils with a cross-β structure and supports the validity of in vitro propagation experiments using artificially formed amyloid fibrils of α-syn. Notably, our finding supports the concept that PD is a type of amyloidosis, a disease featuring the accumulation of amyloid fibrils of α-syn.

scholarly journals Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells

2021 ◽  
Vol 22 (21) ◽  
pp. 11455
Author(s):  
Emma Lorentzon ◽  
Istvan Horvath ◽  
Ranjeet Kumar ◽  
Joana Isabel Rodrigues ◽  
Markus J. Tamás ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Yeast Cells ◽  
Amyloid Formation ◽  
Amyloid Fibers ◽  
Force Microscopy ◽  
Atomic Force ◽  
In Vitro Characterization ◽  
Underlying Mechanisms

Exposure to heavy metals, including arsenic and cadmium, is associated with neurodegenerative disorders such as Parkinson’s disease. However, the mechanistic details of how these metals contribute to pathogenesis are not well understood. To search for underlying mechanisms involving α-synuclein, the protein that forms amyloids in Parkinson’s disease, we here assessed the effects of arsenic and cadmium on α-synuclein amyloid formation in vitro and in Saccharomyces cerevisiae (budding yeast) cells. Atomic force microscopy experiments with acetylated human α-synuclein demonstrated that amyloid fibers formed in the presence of the metals have a different fiber pitch compared to those formed without metals. Both metal ions become incorporated into the amyloid fibers, and cadmium also accelerated the nucleation step in the amyloid formation process, likely via binding to intermediate species. Fluorescence microscopy analyses of yeast cells expressing fluorescently tagged α-synuclein demonstrated that arsenic and cadmium affected the distribution of α-synuclein aggregates within the cells, reduced aggregate clearance, and aggravated α-synuclein toxicity. Taken together, our in vitro data demonstrate that interactions between these two metals and α-synuclein modulate the resulting amyloid fiber structures, which, in turn, might relate to the observed effects in the yeast cells. Whilst our study advances our understanding of how these metals affect α-synuclein biophysics, further in vitro characterization as well as human cell studies are desired to fully appreciate their role in the progression of Parkinson’s disease.

scholarly journals α-synuclein pathogenesis in hiPSC models of Parkinson’s Disease

2021 ◽  
Author(s):  
Leo R Quinlan ◽  
Jara Maria Baena-Montes ◽  
Sahar Avazzadeh
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Modeling ◽  
Viral Vector ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Model Systems ◽  
The Brain

α-synuclein is an increasingly prominent player in the pathology of a variety of neurodegenerative conditions. Parkinson’s disease (PD) is a neurodegenerative disorder that affects mainly the dopaminergic neurons in the substantia nigra of the brain. Typical of PD pathology is the finding of protein aggregations termed ‘Lewy bodies’ in the brain regions affected. α-synuclein is implicated in many disease states including dementia with Lewy bodies and Alzheimer’s disease. However, PD is the most common synucleinopathy and continues to be a significant focus of PD research in terms of the α-synuclein Lewy body pathology. Mutations in several genes are associated with PD development including SNCA, which encodes α-synuclein. A variety of model systems have been employed to study α-synuclein physiology and pathophysiology in an attempt to relate more closely to PD pathology. These models include cellular and animal system exploring transgenic technologies, viral vector expression and knockdown approaches, and models to study the potential prion protein-like effects of α-synuclein. The current review focuses on human induced pluripotent stem cell (iPSC) models with a specific focus on mutations or multiplications of the SNCA gene. iPSCs are a rapidly evolving technology with huge promise in the study of normal physiology and disease modeling in vitro. The ability to maintain a patient's genetic background and replicate similar cell phenotypes make iPSCs a powerful tool in the study of neurological diseases. This review focus on the current knowledge about α-synuclein physiological function as well as its role in PD pathogenesis based on human iPSC models.

scholarly journals C-terminal α-synuclein truncations are linked to cysteine cathepsin activity in Parkinson's disease

2019 ◽  
Vol 294 (25) ◽  
pp. 9973-9984 ◽  
Author(s):  
Ryan P. McGlinchey ◽  
Shannon M. Lacy ◽  
Katherine E. Huffer ◽  
Nahid Tayebi ◽  
Ellen Sidransky ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Amino Acids ◽  
Parkinson's Disease ◽  
Amyloid Fibrils ◽  
Lewy Bodies ◽  
Amyloid Formation ◽  
Pathological Feature ◽  
Cysteine Cathepsins ◽  
Cathepsin Activity ◽  
Cysteine Cathepsin

A pathological feature of Parkinson's disease (PD) is Lewy bodies (LBs) composed of α-synuclein (α-syn) amyloid fibrils. α-Syn is a 140 amino acids–long protein, but truncated α-syn is enriched in LBs. The proteolytic processes that generate these truncations are not well-understood. On the basis of our previous work, we propose that these truncations could originate from lysosomal activity attributable to cysteine cathepsins (Cts). Here, using a transgenic SNCAA53T mouse model, overexpressing the PD-associated α-syn variant A53T, we compared levels of α-syn species in purified brain lysosomes from nonsymptomatic mice with those in age-matched symptomatic mice. In the symptomatic mice, antibody epitope mapping revealed enrichment of C-terminal truncations, resulting from CtsB, CtsL, and asparagine endopeptidase. We did not observe changes in individual cathepsin activities, suggesting that the increased levels of C-terminal α-syn truncations are because of the burden of aggregated α-syn. Using LC-MS and purified α-syn, we identified C-terminal truncations corresponding to amino acids 1–122 and 1–90 from the SNCAA53T lysosomes. Feeding rat dopaminergic N27 cells with exogenous α-syn fibrils confirmed that these fragments originate from incomplete fibril degradation in lysosomes. We mimicked these events in situ by asparagine endopeptidase degradation of α-syn fibrils. Importantly, the resulting C-terminally truncated fibrils acted as superior seeds in stimulating α-syn aggregation compared with that of the full-length fibrils. These results unequivocally show that C-terminal α-syn truncations in LBs are linked to Cts activities, promote amyloid formation, and contribute to PD pathogenesis.

Potential Treatment of Parkinson's Disease, Using Last-Generation Carbon Nanotubes: A Bimolecular In-Silico Study

2020 ◽  
Author(s):  
Ehsan Alimohammadi ◽  
Arash Nikzad ◽  
Mohamad Khedri ◽  
Milad Rezaeian ◽  
Ahmad Miri Jahromi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Molecular Dynamics ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Molecular Study ◽  
Amyloid Formation ◽  
Simulation Tools ◽  
Study Results ◽  
Underlying Mechanisms ◽  
Synuclein Proteins

Abstract Background: Parkinson's disease (PD) is one of the most common neurodegenerative disorders. One of the underlying mechanisms of the disease is the accumulation of α-synuclein protein aggregates, including amyloids and Lewy bodies in the brain, resulting in the death of dopaminergic cells in the substantia nigra. The current treatments for PD are mainly focused on replacing dopamine. However, if these medications are stopped, the severity of PD will increase. Moreover, the drugs used for the treatment of PD are associated with considerable side effects and dietary restrictions. Therefore, necessary studies to develop more effective medications for PD seem to be indispensable. To prevent the progression of PD, avoiding the development of α-synuclein amyloids could be proposed. Methods: In this study, the effects of three last-generation nanotube-based structures on α-synuclein amyloid formation were investigated for the first time employing Molecular Dynamics (MD) simulation tools. Molecular dynamics provide a deep insight into atomic interactions and can well study α-synuclein amyloid formation at the atomic and molecular scales.Results: The molecular study results indicated that all of the nanotubes studied in this work, had strong energy interactions with α-synuclein. Therefore, nanotubes using phosphorus, nitrogen and boron dopants, have great potential to prevent α-synuclein amyloid formation. Among these nanotubes, phosphorus-doped carbon nanotube (P-CNT) has the most substantial interactions with α-synuclein. The P-CNT caused more hydrogen bonds to be formed between water and α-synuclein molecules. This phenomenon leads to a decrease in the compactness, stability, and contact area of α-synuclein proteins, which results in considerable changes in the secondary structure of α-synuclein.Conclusions: Doping nanotubes especially P-CNT could be very effective for preventing the α-synuclein amyloid formation and hence, halting the progression of PD. This molecular study paves the way for the use of the Doping nanotubes in the treatment of PD. These structures are highly tunable and flexible. Therefore, the results of this work can be developed to computational, experimental and clinical levels.

scholarly journals Couldα-Synuclein Amyloid-Like Aggregates Trigger a Prionic Neuronal Invasion?

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Maria Antònia Busquets ◽  
Alba Espargaró ◽  
Joan Estelrich ◽  
Raimon Sabate
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disease ◽  
Prion Protein ◽  
Intracellular Localization ◽  
Lewy Bodies ◽  
Key Factors ◽  
Neuronal Toxicity

Parkinson’s disease (PD), a progressive neurodegenerative disease primarily affecting voluntary and controlled movement, is characterized by abnormal accumulations ofα-synuclein (α-syn) in intraneuronal Lewy bodies. In the last years, the increased number of evidences from both thein vitroandin vivostudies has shown the ability ofα-syn to misfold in amyloid conformations and to spread via neuron-to-neuron transmission, suggesting a prion-like behaviour. However, in contrast to prion protein (PrP),α-syn transmission is far from neuronal invasion. The high neuronal toxicity of both mature fibres and oligomeric species, as well as the intracellular localization of the protein and the difficulty to be secreted, could be key factors impeding the prion ability ofα-syn aggregates.

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