Metal imbalance and compromised antioxidant function are early changes in prion disease

Thackray, Alana M.; Knight, Rob; Haswell, Stephen J.; Mathiason, Candace K.; Brown, David R.

doi:10.1042/0264-6021:3620253

Cited by 129 publications

(124 citation statements)

References 22 publications

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“…10 A combined decrease in Cu with an increase in Mn in blood and brain has been detected prior to disease onset in BSE infected cattle and Scrapie-infected mice and sheep, as well as in brain synaptosomes of Scrapie-infected mice. 18,23,24 Similar changes in liver have been reported in chronic wasting disease (CWD) infected free-ranging mule deer; while low levels of magnesium (Mg) have been reported in the brain of CWD-infected elk. 25,26 Metal analyses of blood and tissue have been suggested as surrogate markers for prion infection.…”

Section: Introductionmentioning

confidence: 71%

“…Our results differ from previous findings where mice and ruminants with neurodegenerative disorders like CWD, scrapie and BSE showed lower levels of Mg and Cu, higher levels of Mn, and no significant changes in Fe. 18,23,25,26 This suggests that results among species infected with TSEs should not be extrapolated.…”

Section: Discussionmentioning

confidence: 99%

“…16 PrP Sc , on the other hand, is the pathogenic agent in all TSEs, as changes in conformation of PrP C to PrP Sc induce pathological modifications such as: neurotoxicity due to disruption of PrP C normal function and imbalance in metal homeostasis in the brain, physical damage of membranes by PrP Sc aggregation, and apoptosis as a result of intracellular PrP Sc accumulation. 10,[17][18][19] Moreover, TSE neurotoxicity, associated with imbalance in brain homeostasis and deregulation of metals, has been previously observed for other neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). 9 PrP C -metal interactions differ with each metal and may play a physiological or pathological role.…”

Section: Introductionmentioning

confidence: 99%

“…19,22 Moreover, the loss of PrP C functions may increase intracellular free radicals and oxidative damage. 9,18 TSEs like Scrapie and Sporadic CreutzfeldtJacob disease have been linked to changes in Fe metabolism that contribute to accumulation of PrP Sc , sequestration of Fe in PrP Sc -ferritin complexes, and neurotoxicity associated to upregulation of Fe intake into the brain. 10,17 Furthermore, Fe binding to PrP C contributes to conformational changes that provide PrP Sc stability and resistance to proteinase K (PK) digestion.…”

Section: Introductionmentioning

confidence: 99%

“…25,26 Metal analyses of blood and tissue have been suggested as surrogate markers for prion infection. 18,23,25 Besides the analysis of TSE neurotoxicity associated with imbalance in brain homeostasis and deregulation of metals, many studies have considered the role of environmental factors, such as soil properties, on TSE transmission.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Metals in obex and retropharyngeal lymph nodes of Illinois white-tailed deer and their variations associated with CWD status

Rivera

Novakofski

Weng

et al. 2015

Prion

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ABSTRACT. Prion proteins (PrP C ) are cell membrane glycoproteins that can be found in many cell types, but specially in neurons. Many studies have suggested PrP C 's participation in metal transport and cellular protection against stress in the central nervous system (CNS). On the other hand PrP Sc , the misfolded isoform of PrP C and the pathogenic agent in transmissible spongiform encephalopathies (TSE), has been associated with brain metal dyshomeostasis in prion diseases. Thus, changes in metal concentration associated with protein misfolding and aggregation have been reported for human and animal prion diseases, as well as for other neurodegenerative disorders, such as Parkinson's and Alzheimer's disease. The use of metal concentrations in tissues as surrogate markers for early detection of TSEs has been suggested. Studies on the accumulation of metals in free-ranging white-tailed deer have not been conducted. This study established concentrations of copper, iron, manganese, and magnesium in 2 diagnostic tissues used for CWD testing (obex and retropharyngeal lymph nodes (RLN)). We compared these concentrations between tissues and in relation to CWD status. We established reference intervals (RIs) for these metals and explored their ability to discriminate between CWD-positive and CWD-negative animals. Our results indicate that independent of CWD status, white-tailed deer accumulate higher concentrations of Fe, Mn and Mg in Ó Nelda A Rivera, Jan Novakofski, Hsin-Yi Weng, Amy Kelly, Damian Satterthwaite-Phillips, Marilyn O Ruiz, and Nohra Mateus-Pinilla *Correspondence to: Nohra Mateus-Pinilla; Email:nohram@illinois.edu Received November 21, 2014; Revised January 25, 2015; Accepted February 9, 2015. Color versions of one or more figures in this article can be found online at www.tandfonline.com/kprn. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. ISSN: 1933-6896 print / 1933-690X online DOI: 10.1080/19336896.2015 RLN than in obex. White-tailed deer infected with CWD accumulated significantly lower concentrations of Mn and Fe than CWD-negative deer. These patterns differed from other species infected with prion diseases. Overlapping values between CWD positive and negative groups indicate that evaluation of these metals in obex and RLN may not be appropriate as a diagnostic tool for CWD infection in white-tailed deer. Because the CWD-negative deer were included in constructing the RIs, high specificities were expected and should be interpreted with caution. Due to the low sensitivity derived from the RIs, we do not recommend using metal concentrations for disease discrimination.Prion, 9:48-58, 2015 Published with license by Taylor & Francis Group, LLC

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Section: Introductionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Metals in obex and retropharyngeal lymph nodes of Illinois white-tailed deer and their variations associated with CWD status

Rivera

Novakofski

Weng

et al. 2015

Prion

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Structural and Dynamic Characterization of Copper(II) Binding of the Human Prion Protein Outside the Octarepeat Region

Berti

Gaggelli

Guerrini

et al. 2007

Chemistry A European J

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Human prion protein (hPrP) fragments encompassing the 91-120 region, namely hPrP92-100 (SP1), hPrP106-113 (SP2), hPrP91-120 (LP1), and hPrP91-114 (LP2), were considered for delineation of the Cu(II)-binding site(s). NMR and EPR spectroscopy results obtained from LP1 or LP2 were compared with those obtained from SP1 and SP2. The coexistence of two binding sites, one centered at His96 and the other at His111, was evidenced and ratified by ESI mass spectrometry at low and high metal:peptide ratios. While room-temperature NMR spectroscopy data were consistent with the binding site centered on His111 being approximately fourfold stronger than that centered on His96, low-temperature EPR spectroscopy results yielded evidence for the opposite trend. This disagreement, which has also occurred in the literature, was clarified by temperature-dependent molecular dynamics runs that demonstrated Met112 approaching the metal at room temperature, a process that is expected to stabilize the His111-centered binding site through hydrophobic shielding of the metal coordination sphere.

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Cross‐Talk Between the Octarepeat Domain and the Fifth Binding Site of Prion Protein Driven by the Interaction of Copper(II) with the N‐terminus

Natale

Turi

Pappalardo

et al. 2015

Chemistry A European J

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Prion diseases are a group of neurodegenerative diseases based on the conformational conversion of the normal form of the prion protein (PrP(C)) to the disease-related scrapie isoform (PrP(Sc)). Copper(II) coordination to PrP(C) has attracted considerable interest for almost 20 years, mainly due to the possibility that such an interaction would be an important event for the physiological function of PrP(C). In this work, we report the copper(II) coordination features of the peptide fragment Ac(PEG11)3PrP(60-114) [Ac = acetyl] as a model for the whole N-terminus of the PrP(C) metal-binding domain. We studied the complexation properties of the peptide by means of potentiometric, UV/Vis, circular dichroism and electrospray ionisation mass spectrometry techniques. The results revealed that the preferred histidyl binding sites largely depend on the pH and copper(II)/peptide ratio. Formation of macrochelate species occurs up to a 2:1 metal/peptide ratio in the physiological pH range and simultaneously involves the histidyl residues present both inside and outside the octarepeat domain. However, at increased copper(II)/peptide ratios amide-bound species form, especially within the octarepeat domain. On the contrary, at basic pH the amide-bound species predominate at any copper/peptide ratio and are formed preferably with the binding sites of His96 and His111, which is similar to the metal-binding-affinity order observed in our previous studies.

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Metal imbalance and compromised antioxidant function are early changes in prion disease

Cited by 129 publications

References 22 publications

Metals in obex and retropharyngeal lymph nodes of Illinois white-tailed deer and their variations associated with CWD status

Metals in obex and retropharyngeal lymph nodes of Illinois white-tailed deer and their variations associated with CWD status

Structural and Dynamic Characterization of Copper(II) Binding of the Human Prion Protein Outside the Octarepeat Region

Cross‐Talk Between the Octarepeat Domain and the Fifth Binding Site of Prion Protein Driven by the Interaction of Copper(II) with the N‐terminus

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