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

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.

Download Full-text

Fibroblast Growth Factor 20 Gene Polymorphism in Parkinson’s Disease in Asian Population: A Meta-Analysis

Genes ◽

10.3390/genes12050674 ◽

2021 ◽

Vol 12 (5) ◽

pp. 674

Author(s):

Han-Lin Chiang ◽

Yih-Ru Wu ◽

Yi-Chun Chen ◽

Hon-Chung Fung ◽

Chiung-Mei Chen

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Meta Analysis ◽

Lewy Bodies ◽

Asian Population ◽

Protective Role ◽

Lewy Neurites ◽

Chinese Populations ◽

Study Results

Parkinson’s disease (PD) is a neurodegenerative disease with the pathological hallmark of Lewy bodies and Lewy neurites composed of α-synuclein. The SNP rs591323 is one of the risk loci located near the FGF20 gene that has been implicated in PD. The variation of FGF20 in the 3′ untranslated region was shown to increase α-synuclein expression. We examined the association of rs591323 with the risk of PD in a Taiwanese population and conducted a meta-analysis, including our study and two other studies from China, to further confirm the role of this SNP in Taiwanese/Chinese populations. A total of 586 patients with PD and 586 health controls (HCs) were included in our study. We found that the minor allele (A) and the AA + GA genotype under the dominant model are significantly less frequent in PD than in controls. The meta-analysis consisted of 1950 patients with PD and 2073 healthy controls from three studies. There was significant association between rs591323 and the risk of PD in the additive (Z = −3.96; p < 0.0001) and the dominant models (Z = −4.01; p < 0.0001). Our study results and the meta-analysis support the possible protective role of the rs591323 A allele in PD in Taiwanese/Chinese populations.

Download Full-text

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

International Journal of Molecular Sciences ◽

10.3390/ijms222111455 ◽

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.

Download Full-text

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

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.008930 ◽

2019 ◽

Vol 294 (25) ◽

pp. 9973-9984 ◽

Cited By ~ 11

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.

Download Full-text

Pesticides and Parkinson’s Disease

The Scientific World JOURNAL ◽

10.1100/tsw.2001.35 ◽

2001 ◽

Vol 1 ◽

pp. 207-208 ◽

Cited By ~ 14

Author(s):

Todd B. Sherer ◽

Ranjita Betarbet ◽

J. Timothy Greenamyre

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Selective Death ◽

Underlying Mechanisms ◽

Common Neurodegenerative Disorder

Parkinson’s disease (PD), a common neurodegenerative disorder affects approximately 1% of the population over 65. PD is a late-onset progressive motor disease characterized by tremor, rigidity (stiffness), and bradykinesia (slowness of movement). The hallmark of PD is the selective death of dopamine-containing neurons in the substantia nigra pars compacta which send their projections to the striatum and the presence of cytoplasmic aggregates called Lewy bodies [1-2]. Most cases of PD are sporadic but rare cases are familial, with earlier onset. The underlying mechanisms and causes of PD still remain unclear.

Download Full-text

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

Nanomedicine ◽

10.2217/nnm-2020-0372 ◽

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.

Download Full-text

Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21197182 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7182

Author(s):

Rui Wang ◽

Hongyang Sun ◽

Guanghui Wang ◽

Haigang Ren

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Lysine Acetylation ◽

Nonhistone Proteins ◽

Advantages And Disadvantages ◽

Genetic And Environmental Factors ◽

Underlying Mechanisms ◽

Lysine Deacetylases

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. The neuropathological features of PD are selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta, deficiencies in striatal dopamine levels, and the presence of intracellular Lewy bodies. Interactions among aging and genetic and environmental factors are considered to underlie the common etiology of PD, which involves multiple changes in cellular processes. Recent studies suggest that changes in lysine acetylation and deacetylation of many proteins, including histones and nonhistone proteins, might be tightly associated with PD pathogenesis. Here, we summarize the changes in lysine acetylation of both histones and nonhistone proteins, as well as the related lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), in PD patients and various PD models. We discuss the potential roles and underlying mechanisms of these changes in PD and highlight that restoring the balance of lysine acetylation/deacetylation of histones and nonhistone proteins is critical for PD treatment. Finally, we discuss the advantages and disadvantages of different KAT/KDAC inhibitors or activators in the treatment of PD models and emphasize that SIRT1 and SIRT3 activators and SIRT2 inhibitors are the most promising effective therapeutics for PD.

Download Full-text

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

10.1101/2020.06.08.140798 ◽

2020 ◽

Cited By ~ 3

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.

Download Full-text