The prion protein and its ligands: Insights into structure-function relationships

Shafiq, Mohsin; Vela, Stefano Da; Amin, Ladan; Younas, Neelam; Zerr, Inga; Altmeppen, Hermann; Svergun, D. I.; Glatzel, Markus

doi:10.1016/j.bbamcr.2022.119240

Cited by 12 publications

(10 citation statements)

References 221 publications

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“…The latter increases the α-cleavage-like processing of PrP C on EVs (therefore increasing the amount of C1 fragment attached to the EVs, although they are already physiologically enriched in PrP-C1 as shown (Brenna et al , 2020). Moreover, this artificial modification observed here would induce the release of the N-terminal part of PrP C , which typically interacts with diverse ligands, potentially modulating their functions (see (Shafiq et al , 2022)), such as synaptic receptors in epilepsy (Carulla et al , 2011), the beta-amyloid in Alzheimer’s disease (Laurén et al , 2009; Resenberger et al , 2011; Falker et al , 2016), the α-synuclein in Parkinson models (Urrea et al , 2018) or the misfolded PrP in Prion diseases (Turnbaugh et al , 2011). Moreover, the lack of this N-terminal part could also affect the interaction of EVs with recipient cells and their uptake since it has been shown that PrP C expression modulates the EV uptake (Brenna et al , 2020).…”

Section: Discussionmentioning

confidence: 99%

Efficient enzyme-free isolation of brain-derived extracellular vesicles

Matamoros-Angles,

Karadjuzovic,

Mohammadi

et al. 2024

Preprint

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Extracellular vesicles (EVs) have gained significant attention as pathology mediators and potential diagnostic tools for neurodegenerative diseases. However, isolation of brain-derived EVs (BDEVs) from tissue remains challenging, often involving enzymatic digestion steps that may compromise the integrity of EV proteins and overall functionality. Here, we describe that collagenase digestion, commonly used for BDEV isolation, produces undesired protein cleavage of EV-associated proteins in brain tissue homogenates and cell-derived EVs. In order to avoid this effect, we studied the possibility of isolating BDEVs with a reduced amount of collagenase or without any protease. Characterization of the isolated BDEVs revealed their characteristic morphology and size distribution with both approaches. However, we revealed that even minor enzymatic digestion induces 'artificial' proteolytic processing in key BDEV markers, such as Flotillin-1, CD81, and the cellular prion protein (PrPC), whereas avoiding enzymatic treatment completely preserves their integrity. We found no differences in mRNA and protein content between non-enzymatically and enzymatically isolated BDEVs, suggesting that we are purifying the same BDEV populations with both approaches. Intriguingly, the lack of Golgi marker GM130 signal, often referred to as contamination contamination-negative marker in EV preparations, seems to result from enzymatic digestion rather than from its actual absence in BDEV samples. Overall, we show that non-enzymatic isolation of EVs from brain tissue is possible and avoids artificial pruning of proteins while achieving a high BDEV yield and purity. This protocol will help to understand the functions of BDEV in a near-physiological setting, thus opening new research approaches.

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Section: Discussionmentioning

confidence: 99%

Efficient enzyme-free isolation of brain-derived extracellular vesicles

Matamoros-Angles,

Karadjuzovic,

Mohammadi

et al. 2024

Preprint

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“…Other reported PrP c signaling pathways that are important in the regulation of chemical neurotransmission include phosphoinositide 3 kinase (PI3K), Akt protein kinase A (PKA), MAP kinase ERK1/2, mammalian target of rapamycin (mTOR) and calcium signaling—molecular mechanisms underlying the pathophysiology and treatment of mood disorders [ 23 , 24 , 25 ].…”

Section: The Function Of the Prion Protein (Prp C ...mentioning

confidence: 99%

New Light on Prions: Putative Role of PrPc in Pathophysiology of Mood Disorders

Chrobak,

Pańczyszyn-Trzewik,

Król

et al. 2024

IJMS

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Mood disorders are highly prevalent and heterogenous mental illnesses with devastating rates of mortality and treatment resistance. The molecular basis of those conditions involves complex interplay between genetic and environmental factors. Currently, there are no objective procedures for diagnosis, prognosis and personalization of patients’ treatment. There is an urgent need to search for novel molecular targets for biomarkers in mood disorders. Cellular prion protein (PrPc) is infamous for its potential to convert its insoluble form, leading to neurodegeneration in Creutzfeldt-Jacob disease. Meanwhile, in its physiological state, PrPc presents neuroprotective features and regulates neurotransmission and synaptic plasticity. The aim of this study is to integrate the available knowledge about molecular mechanisms underlying the impact of PrPc on the pathophysiology of mood disorders. Our review indicates an important role of this protein in regulation of cognitive functions, emotions, sleep and biological rhythms, and its deficiency results in depressive-like behavior and cognitive impairment. PrPc plays a neuroprotective role against excitotoxicity, oxidative stress and inflammation, the main pathophysiological events in the course of mood disorders. Research indicates that PrPc may be a promising biomarker of cognitive decline. There is an urgent need of human studies to elucidate its potential utility in clinical practice.

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“…Cellular prion protein (PrP) that encoded by the PRPN gene is a highly conserved glycoprotein found in all mammalian cells [9,10]. Besides its diverse cellular functions, PrP also acts a potential activator of the MDR phenotype by upregulating Pgp-1 in cancer cells [11,12].…”

Section: Introductionmentioning

confidence: 99%

Effect of siRNA-promoted Silencing of Prion Protein on Doxorubicin-induced Cell Death Machineries in Human Adriamycin-resistant Small Cell Lung Cancer Cell Line H69AR

Kadınşah,

Öztel,

Tuğrul

et al. 2023

Preprint

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Background Multidrug resistance is one of major challenges in cancer therapy. Recent data have proposed that among its many cellular functions, prion protein (PrP) is also involved in the acquisition of a multidrug resistance phenotype of cancer cells. In this study, we examined the effect of PrP on doxorubicin-induced cell death in the human adriamycin-resistant small cell lung cancer cell line H69AR. Methods We established an experimental design with a series of groups including knockdown of PrP expression in H69AR cells by siRNA (siRNA group), doxorubicin treatment at IC50 concentration (Doxo IC50 group) and combination of siRNA transfection/doxorubicin IC50 treatment (siRNA/Doxo IC50 group). qRT-PCR and immunocytochemistry analyses were performed for PrP, CD44, Bax and Beclin-1 expressions. Results siRNA transfection and co-delivery of siRNA transfection/doxorubicin treatment decreased the PrP mRNA expression and immunofluorescence signals for PrP. However, doxorubicin treatment at IC50 concentration increased the PrP levels. Besides, the increased expression of CD44, Bax and Beclin-1 proteins was observed in all three groups. Monodansylcadaverine results indicated that the number of autophagic vacuoles was increased in all the experimental conditions. Conclusions Our results suggest that knockdown of PrP in H69AR cells may ameliorate the doxorubicin-induced cell death machineries such as apoptosis and autophagy. In conclusion, the knockdown of PrP may be an attractive strategy for the treatment of drug-resistant cancers to improve the effect of conventional chemotherapeutics.

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The prion protein and its ligands: Insights into structure-function relationships

Cited by 12 publications

References 221 publications

Efficient enzyme-free isolation of brain-derived extracellular vesicles

Efficient enzyme-free isolation of brain-derived extracellular vesicles

New Light on Prions: Putative Role of PrPc in Pathophysiology of Mood Disorders

Effect of siRNA-promoted Silencing of Prion Protein on Doxorubicin-induced Cell Death Machineries in Human Adriamycin-resistant Small Cell Lung Cancer Cell Line H69AR

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