Influence of gold–bipyridyl derivants on aggregation and disaggregation of the prion neuropeptide PrP106–126

Neurodegenerative diseases are linked to a systemic enzyme resistance of toxic aggregated molecules and their pathological consequences. This paper presents a unique phenomenon that Philodina acuticornis, a bdelloid rotifer, is able to catabolize different types of neurotoxic peptide and protein aggregates (such as beta-amyloids /Aβ/, alpha-synuclein, and prion) without suffering any damage. P. acuticornis is capable of using these aggregates as an exclusive energy source (i.e., as ‘food’, identified in the digestive system and body) in a hermetically isolated microdrop environment, increasing their survival. As regards Aβ1–42, five other bdelloid rotifer species were also found to be able to perform this phenomenon. Based on our experiments, the Aβ1–42-treated bdelloid rotifers demonstrate significantly increased survival (e.g. mean lifespan = 51 ± 2.71 days) compared to their untreated controls (e.g. mean lifespan = 14 ± 2.29 days), with similar improvements in a variety of phenotypic characteristics. To our knowledge, no other animal species have so far been reported to have a similar capability. For all other microscopic species tested, including monogonant rotifers and non-rotifers, the treatment with Aβ1–42 aggregates proved to be either toxic or simply ineffective. This paper describes and proves the existence of an unprecedented in vivo catabolic capability of neurotoxic aggregates by bdelloid rotifers, with special focus on P. acuticornis. Our results may provide the basis for a new preclinical perspective on therapeutic research in human neurodegenerative diseases.

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“…Our in vitro results (Fig. 2 ) were in line with our a priori expectations and the academic literature [ 45 , 56 ].…”

Section: Discussionsupporting

confidence: 91%

Exceptional in vivo catabolism of neurodegeneration-related aggregates

Datki

Oláh

Hortobágyi

et al. 2018

acta neuropathol commun

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“…[25][26][27][28][29][30][31][32] In the present study, IC 50 values were also determined to compare the inhibition ability of different ruthenium complexes on the preformed PrP106-126 fibrils. Ruthenium complexes can significantly affect the formation of the PrP106-126 amyloid structures as determined using the ThT assay.…”

Section: Effective Inhibition Of Ruthenium Complexes Upon Prp106-126 mentioning

confidence: 99%

Inhibitory effects of NAMI-A-like ruthenium complexes on prion neuropeptide fibril formation

et al. 2015

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Prion diseases are a group of infectious and fatal neurodegenerative disorders caused by the conformational conversion of a cellular prion protein (PrP) into its abnormal isoform PrP(Sc). PrP106-126 resembles PrP(Sc) in terms of physicochemical and biological characteristics and is used as a common model for the treatment of prion diseases. Inhibitory effects on fibril formation and neurotoxicity of the prion neuropeptide PrP106-126 have been investigated using metal complexes as potential inhibitors. Nevertheless, the binding mechanism between metal complexes and the peptide remains unclear. The present study is focused on the interaction of PrP106-126 with NAMI-A and NAMI-A-like ruthenium complexes, including KP418, KP1019, and KP1019-2. Results demonstrated that these ruthenium complexes could bind to PrP106-126 in a distinctive binding mode through electrostatic and hydrophobic interactions. NAMI-A-like ruthenium complexes can also effectively inhibit the aggregation and fibril formation of PrP106-126. The complex KP1019 demonstrated the optimal inhibitory ability upon peptide aggregation, and cytotoxicity because of its large aromatic ligand contribution. The studied complexes could also regulate the copper redox chemistry of PrP106-126 and effectually inhibit the formation of reactive oxygen species. Given these findings, ruthenium complexes with relatively low cellular toxicity may be used to develop potential pharmaceutical products against prion diseases.

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“…Beyond Pt(II) complexes, other metal complexes have been used as inhibitors of amyloid fiber formation. Due to the ligand field similarities between Pd(II), Au(III), and Pt(II) compounds, the ability of Pd(II) and Au(III) compound to inhibit the fiber formation has been investigated [11][12][13][14][15]. Pd(II) compounds can exchange ligands 10 5 times faster than their Pt(II) analogues [16], enhancing their capability to interact with the cellular components such as sulfur-donor biomolecules.…”

Section: Introductionmentioning

confidence: 99%

Role of the Metal Center in the Modulation of the Aggregation Process of Amyloid Model Systems by Square Planar Complexes Bearing 2-(2′-pyridyl)benzimidazole Ligands

et al. 2019

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The effect of analogue Pd(II)-, Pt(II)-, and Au(III) compounds featuring 2-(2’-pyridyl)benzimidazole on the aggregation propensity of amyloid-like peptides derived from Aβ and from the C-terminal domain of nucleophosmin 1 was investigated. Kinetic profiles of aggregation were evaluated using thioflavin binding assays, whereas the interactions of the compounds with the peptides were studied by UV-Vis absorption spectroscopy and electrospray ionization mass spectrometry. The results indicate that the compounds modulate the aggregation of the investigated peptides using different mechanisms, suggesting that the reactivity of the metal center and the physicochemical properties of the metals (rather than those of the ligands and the geometry of the metal compounds) play a crucial role in determining the anti-aggregation properties.

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Influence of gold–bipyridyl derivants on aggregation and disaggregation of the prion neuropeptide PrP106–126

Cited by 20 publications

References 61 publications

Exceptional in vivo catabolism of neurodegeneration-related aggregates

Exceptional in vivo catabolism of neurodegeneration-related aggregates

Inhibitory effects of NAMI-A-like ruthenium complexes on prion neuropeptide fibril formation

Role of the Metal Center in the Modulation of the Aggregation Process of Amyloid Model Systems by Square Planar Complexes Bearing 2-(2′-pyridyl)benzimidazole Ligands

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