Review: PrP 106‐126 – 25 years after

Forloni, Gianluigi; Chiesa, Roberto; Bugiani, Orso; Salmona, Mario; Tagliavini, Fabrizio

doi:10.1111/nan.12538

Cited by 20 publications

(18 citation statements)

References 116 publications

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“…PrP 106-126 is widely used as a model for studying PrP Sc neurotoxicity because it leads to neuronal apoptosis and cytotoxicity [24][25][26]. In our study, Bax accumulation in and the release of cytochrome c from mitochondria were observed, while the expression of Bcl-2, an antiapoptotic factor, was decreased.…”

Section: Discussionmentioning

confidence: 48%

Melatonin regulates mitochondrial dynamics and alleviates neuron damage in prion diseases

Zhang

Zhao

et al. 2020

Aging

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Prion diseases are neurodegenerative diseases associated with neuron damage and behavioral disorders in animals and humans. Melatonin is a potent antioxidant and is used to treat a variety of diseases. We investigated the neuroprotective effect of melatonin on prion-induced damage in N2a cells. N2a cells were pretreated with 10 μM melatonin for 1 hour followed by incubation with 100 μM PrP 106-126 for 24 hours. Melatonin markedly alleviated PrP 106-126-induced apoptosis of N2a cells, and inhibited PrP 106-126-induced mitochondrial abnormality and dysfunction, including mitochondrial fragmentation and overproduction of reactive oxygen species (ROS), suppression of ATP, reduced mitochondrial membrane potential (MMP), and altered mitochondrial dynamic proteins dynamin-related protein 1 (DRP1) and optic atrophy protein 1 (OPA1). Our findings identify that pretreatment with melatonin prevents the deleterious effects of PrPSc on mitochondrial function and dynamics, protects synapses and alleviates neuron damage. Melatonin could be a novel and effective medication in the therapy of prion diseases.

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Section: Discussionmentioning

confidence: 48%

Melatonin regulates mitochondrial dynamics and alleviates neuron damage in prion diseases

Zhang

Zhao

et al. 2020

Aging

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“…The prion peptide PrP106-126 has been widely used as a suitable model peptide because this fragment is soluble in water and exhibits several physicochemical and biological properties similar to those of PrP Sc , such as aggregation in solution, antiproteinase K digestion, and neurotoxicity [42,43]. However, an important argument about PrP peptide 106-126 is the facts that it is not actually a fragment found in the brains of humans or animals with prion diseases [44]. Even we investigated baicalein effect in this study, we will further study the issue using longer fragments or full-length PrP mutant models to examine therapeutic potential of baicalein in prion disease.…”

Section: Discussionmentioning

confidence: 99%

Calcium-dependent serine-threonine phosphatase, calcineurin inactivation mediated by baicalein attenuates prion protein-mediated neuronal cell damage

Hong

Moon

Park

2020

Preprint

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Background: Prion diseases are a group of unvaryingly fatal neurodegenerative disorders characterized by neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Baicalein has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death. Results: In the present study, we investigated whether baicalein attenuates prion peptide-mediated neurotoxicity and reduces calcineurin. We found that baicalein treatment inhibits prion protein-induced apoptosis. Baicalein inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, baicalein increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and baicalein inhibited prion protein-induced neurotoxicity through autophagy flux inhibition. Conclusions: Taken together, this study demonstrated that baicalein attenuated prion peptide-induced neurotoxicity via calcineurin inactivation and autophagic flux reduction, and also suggest that baicalein may be an effective therapeutic drug against neurodegenerative diseases, including prion diseases.

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“…The amyloidogenic prion residues 106–126 [ 756 , 757 ] in the N-terminal domain are characterized by hydrophilic and hydrophobic regions that can increase lipid density and membrane viscosity upon embedding into lipid bilayers [ 758 ]. The prion peptide fragment 106–126 can form heterogenous single cation channels with different conductance and kinetic properties in lipid bilayers, modifying electrolyte homeostasis and affecting cellular functions [ 759 , 760 , 761 ] while the conversion of PrP C to PrP Sc is often associated with membrane abnormalities including decreased membrane fluidity [ 762 ].…”

Section: The Effects Of Melatonin On Lipid Phase Transition Lipid Com...mentioning

confidence: 99%

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

Loh¹,

Reíter

2022

Molecules

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The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.

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Review: PrP 106‐126 – 25 years after

Cited by 20 publications

References 116 publications

Melatonin regulates mitochondrial dynamics and alleviates neuron damage in prion diseases

Melatonin regulates mitochondrial dynamics and alleviates neuron damage in prion diseases

Calcium-dependent serine-threonine phosphatase, calcineurin inactivation mediated by baicalein attenuates prion protein-mediated neuronal cell damage

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

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