Role of Protein Aggregation in Neurodegenerative Diseases

Tutar, Yusuf; Özgür, Aykut; Tutar, Lütfi

doi:10.5772/54487

Cited by 20 publications

(15 citation statements)

References 85 publications

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“…Oxidative stress-damage to proteins, lipids and DNA as a result of toxic reactive oxygen species (ROS)-is a common feature of many neurodegenerative diseases including Parkinson's disease (PD), where it has been linked to both genetic and sporadic forms of the condition [1][2][3]. Numerous neurotoxins used to model PD, such as 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and rotenone, inhibit mitochondrial respiration, resulting in an accumulation of ROS, inducing a form of parkinsonism in both animals and humans [4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

N-Acetylcysteine Nanocarriers Protect against Oxidative Stress in a Cellular Model of Parkinson’s Disease

Mursaleen

Noble

Chan³

et al. 2020

Antioxidants

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Oxidative stress is a key mediator in the development and progression of Parkinson’s disease (PD). The antioxidant n-acetylcysteine (NAC) has generated interest as a disease-modifying therapy for PD but is limited due to poor bioavailability, a short half-life, and limited access to the brain. The aim of this study was to formulate and utilise mitochondria-targeted nanocarriers for delivery of NAC alone and in combination with the iron chelator deferoxamine (DFO), and assess their ability to protect against oxidative stress in a cellular rotenone PD model. Pluronic F68 (P68) and dequalinium (DQA) nanocarriers were prepared by a modified thin-film hydration method. An MTT assay assessed cell viability and iron status was measured using a ferrozine assay and ferritin immunoassay. For oxidative stress, a modified cellular antioxidant activity assay and the thiobarbituric acid-reactive substances assay and mitochondrial hydroxyl assay were utilised. Overall, this study demonstrates, for the first time, successful formulation of NAC and NAC + DFO into P68 + DQA nanocarriers for neuronal delivery. The results indicate that NAC and NAC + DFO nanocarriers have the potential characteristics to access the brain and that 1000 μM P68 + DQA NAC exhibited the strongest ability to protect against reduced cell viability (p = 0.0001), increased iron (p = 0.0033) and oxidative stress (p ≤ 0.0003). These NAC nanocarriers therefore demonstrate significant potential to be transitioned for further preclinical testing for PD.

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Section: Introductionmentioning

confidence: 99%

N-Acetylcysteine Nanocarriers Protect against Oxidative Stress in a Cellular Model of Parkinson’s Disease

Mursaleen

Noble

Chan³

et al. 2020

Antioxidants

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“…Oxidative stress conveyed through the ROS activity causes deleterious effects on biomolecules, including protein oxidation, misfolding and aggregation, DNA damage and mutations, and lipid peroxidation [ 3 , 4 ]. The ROS can also induce changes to the secondary and tertiary structure of various proteins, including myoglobin, human and bovine serum albumins (HSA and BSA), and sunflower protein [ 5 , 6 , 7 , 8 ]. The ROS generated by radiation could also modify the primary structure of the proteins via degradation, cross-linking, and aggregation of polypeptide chains [ 5 ], which results in distortions of the secondary and tertiary structures [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…The ROS generated by radiation could also modify the primary structure of the proteins via degradation, cross-linking, and aggregation of polypeptide chains [ 5 ], which results in distortions of the secondary and tertiary structures [ 6 ]. The critical factor in many age-related diseases, particularly the various neurodegenerative diseases such as Alzheimer, Parkinson, or Huntington diseases, is the oxidation of proteins by the reactive products of radiation, which leads to aggregated or misfolded protein forms as molecular triggers of the given pathologies [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Radioprotective Role of Vitamins C and E against the Gamma Ray-Induced Damage to the Chemical Structure of Bovine Serum Albumin

et al. 2021

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Radioprotective effects of vitamin C and vitamin E as a water-soluble and a lipid-soluble agent, respectively, were investigated at the molecular level during the imposition of gamma radiation-induced structural changes to bovine serum albumin (BSA) at the therapeutic dose of 3 Gy. Secondary and tertiary structural changes of control and irradiated BSA samples were investigated using circular dichroism and fluorescence spectroscopy. The preirradiation tests showed nonspecific and reversible binding of vitamins C and E to BSA. Secondary and tertiary structures of irradiated BSA considerably changed in the absence of the vitamins. Upon irradiation, α-helices of BSA transitioned to beta motifs and random coils, and the fluorescence emission intensity decreased relative to nonirradiated BSA. In the presence of the vitamins C or E, however, the irradiated BSA was protected from these structural changes caused by reactive oxygen species (ROS). The two vitamins exhibited different patterns of attachment to the protein surface, as inspected by blind docking, and their mechanisms of protection were different. The hydrophilicity of vitamin C resulted in the predominant scavenging of ROS in the solvent, whereas hydrophobic vitamin E localized on the nonpolar patches of the BSA surface, where it did not only form a barrier for diffusing ROS but also encountered them as an antioxidant and neutralized them thanks to the moderate BSA binding constant. Very low concentrations of vitamins C or E (0.005 mg/mL) appear to be sufficient to prevent the oxidative damage of BSA.

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“…The anomaly in the protein behavior can be due to mutations, misfolding of the protein, or non-clearance of the protein by degradation pathways leading to accumulation and aggregation. Protein aggregation is linked to several neurodegenerative diseases like amyloid beta aggregation in Alzheimer's disease , aggregates of αsynuclein in Parkinson's disease (1)(2)(3)(4)(5)(6). Over the last few decades, a good amount of work suggests that the misfolding and aggregation of the p53 protein is a pathological condition in cancer (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Variable Mutations at the p53-R273 Oncogenic Hotspot Position Leads to Altered Properties

Garg

Hazra

Sannigrahi

et al. 2019

Preprint

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Mutations in p53 protein, especially in the DNA binding domain is one of the major hallmarks of cancer. The R273 position is a DNA contact position and has several oncogenic variants. Surprisingly, cancer patients carrying different mutant-variants of R273 in p53 have different survival rates indicating that the DNA contact inhibition may not be the sole reason for reduced survival with R273 variants.Here, we probed the structural properties of three major oncogenic variants of the R273: ([R273L],[R273H], and [R273C])p53. Using a series of biophysical, biochemical and theoretical simulation studies, we observe that these oncogenic variants of the p53 not only suffer a loss in DNA binding, but also show distinct structural stabilty, aggregation and toxicity profiles. [R273C]p53 shows maximum amyloidogenicity while [R273L]p53 shows maximum aggregation. Further probe in the aggregation mechanism show that [R273C]p53 aggregation is disulphide mediated whereas hydrophobic interactions dominate self-assembly in [R273L]p53. MD simulation studies clearly show that α-helical intermediates are observed in [R273C]p53 whereas β-sheets are observed for [R273L]p53. Our study indicates that each of the R273 variant has its own distinct property of stability and self-assembly, the molecular basis of which, may lead to different types of cancer pathogenesis in vivo. These studies will aid the design of therapeutic strategies for cancer using residue specific or process specific protein aggregation as target.Statement of significance. The present work stems from an interesting observation that genetic mutations that results in switching of one amino acid to different variants at the same codon show different cancer cell progression. We are trying to understand the molecular reason behind the different gain-offunction opted by these variants. With the help of biophysical and biochemical experiments, and computational studies we have observed that the different thermal stability, unique mechanism of unfolding and self-assembly might be one of the crucial parameters for their different oncogenic effect. These studies thus call for the need of developing therapeutic strategies that consider the resultant mutantvariant as a target rather than mutation position. This is an important lead towards the understanding of cancer.cate that specific therapeutic strategies that precisely target the additional effect of the mutation apart from compromised DNA binding is also required for cancer management and cure.

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Role of Protein Aggregation in Neurodegenerative Diseases

Cited by 20 publications

References 85 publications

N-Acetylcysteine Nanocarriers Protect against Oxidative Stress in a Cellular Model of Parkinson’s Disease

N-Acetylcysteine Nanocarriers Protect against Oxidative Stress in a Cellular Model of Parkinson’s Disease

Radioprotective Role of Vitamins C and E against the Gamma Ray-Induced Damage to the Chemical Structure of Bovine Serum Albumin

Variable Mutations at the p53-R273 Oncogenic Hotspot Position Leads to Altered Properties

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