Bivalent metal ions induce formation of α-synuclein fibril polymorphs with different cytotoxicities

Abstract

Abstractα-Synuclein (α-Syn) aggregates are key components of intracellular inclusion bodies characteristic of Parkinson’s disease (PD) and other synucleinopathies. Metal ions have been considered as the important etiological factors in PD since their interactions with α-Syn alter the kinetics of fibrillation. In the present study, we have systematically explored the effects of Zn2+, Cu2+, Ca2+, and Mg2+ cations on α-Syn fibril formation. Specifically, we determined fibrillation kinetics, size, morphology, and secondary structure of the fibrils and their cytotoxic activity. While all cations accelerate fibrillation, we observed distinct effects of the different ions. For example, Zn2+ induced fibrillation by lower tlag and higher kapp and formation of shorter fibrils, while Ca2+ ions lead to formation of longer fibrils, as evidenced by dynamic light scattering and atomic force microscopy studies. Additionally, the morphology of formed fibrils was different. Circular dichroism and attenuated total reflection-Fourier transform infrared spectroscopies revealed higher contents of β-sheets in fibrils. Interestingly, cell viability studies indicated nontoxicity of α-Syn fibrils formed in the presence of Zn2+ ions, while the fibrils formed in the presence of Cu2+, Ca2+, and Mg2+ were cytotoxic. Our results revealed that α-Syn fibrils formed in the presence of different divalent cations have distinct structural and cytotoxic features.

Harnessing Graphdiyne for Selective Cu2+ Detection: A Promising Tool for Parkinson’s Disease Diagnostics and Pathogenesis

“…Cu-α-synuclein complexes have been observed in vitro to accelerate oligomerization, thereby triggering and/or accelerating PD . In addition, excess Cu 2+ generates large amounts of ROS via the Fenton reaction, and ROS cause unregulated oxidative damage to proteins, lipids, and other cellular components, ultimately leading to neuronal dysfunction and death. , However, after GSH treatment, the cells produced less ROS and less protein, indicating that GSH can also be used as a potential drug for the treatment of PD. The Cu 2+ electrochemical sensor based on the new carbon material GDY provides a key technology for elucidating the chemical basis of PD, and establishes a reliable and promising method for drug screening.…”

Cell-Penetrating Peptides: Promising Therapeutics and Drug-Delivery Systems for Neurodegenerative Diseases

“…The accumulation of amyloid plaques has been associated with a variety of disorders, spanning from neurodegenerative disorders such as Alzheimer's and Parkinson's disease to metabolic diseases such as diabetes. 10,153,154 When tackling complex diseases such as AD, PD, and diabetes, recombinant proteins and gene-therapy strategies show great potential due to their direct impact on genetics and metabolism. 155,156 Nevertheless, there are many serious challenges that should be considered first and foremost.…”

“…These diseases involve soluble peptides or proteins undergoing conformational changes to form stable aggregates, known as amyloids. The accumulation of amyloid plaques has been associated with a variety of disorders, spanning from neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease to metabolic diseases such as diabetes. ,, …”

Modulation of cytotoxic amyloid fibrillation and mitochondrial damage of α-synuclein by catechols mediated conformational changes

“…Clinically, PD is characterized by motor dysfunction that manifests as bradykinesia, rigidity and postural instability. α-synuclein (α-syn) is a 140 amino acid protein that is predominantly localized in the presynaptic terminals of neurons 3 , 4 . Physiological functions of α-syn are associated with synaptic vesicle trafficking and membrane fusion 5 .…”