Recombinant prion protein does not possess SOD-1 activity

Jones, Samantha; Batchelor, Mark; Bhelt, Daljit; Clarke, Anthony R.; Collinge, John; Jackson, Graham S.

doi:10.1042/bj20051236

Cited by 77 publications

(67 citation statements)

References 33 publications

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“…Similarly, tissue cultures of nerve cells derived from the PrP C knockout mouse are less viable and more susceptible to oxidative damage and toxicity caused by agents such as copper and hydrogen peroxide than cells expressing wild-type PrP C (Brown et al, 1997a;Kuwahara et al, 1999). PrP C was hypothesized to act as an antioxidant (Brown and Besinger, 1998;Wong et al, 1999), but recent studies have established that PrP C has no superoxide dismutase activity either in vivo or in vitro (Hutter et al, 2003;Jones et al, 2005). Since numerous studies suggest that, under stress conditions, PrP C has a neuroprotective effect, this raises the question as to whether the neurodegenerative defects observed in scrapieinfected mice are aggravated by the loss of PrP C , as well as the build up of PrP Sc amyloid plaque.…”

Section: Introductionmentioning

confidence: 99%

Cellular prion protein (PrPC) protects neuronal cells from the effect of huntingtin aggregation

Lee

Panzera

Rogawski

et al. 2007

Journal of Cell Science

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The effect of normal cellular prion protein (PrPC) on abnormal protein aggregation was examined by transfecting huntingtin fragments (Htt) into SN56 neuronal-derived cells depleted of PrPC by RNA interference. PrPC depletion caused an increase in both the number of cells containing granules and the number of apoptotic cells. Consistent with the increase in Htt aggregation, PrPC depletion caused an decrease in proteasome activity and a decrease in the activities of cellular defense enzymes compared with control cells whereas reactive oxygen species (ROS) increased more than threefold. Therefore, PrPC may protect against Htt toxicity in neuronal cells by increasing cellular defense proteins, decreasing ROS and increasing proteasome activity thereby increasing Htt degradation. Depletion of endogenous PrPC in non-neuronal Caco-2 and HT-29 cells did not affect ROS levels or proteasome activity suggesting that only in neuronal cells does PrPC confer protection against Htt toxicity. The protective effect of PrPC was further evident in that overexpression of mouse PrPC in SN56 cells transfected with Htt caused a decrease in both the number of cells with Htt granules and the number of apoptotic cells, whereas there was no effect of PrPC expression in non-neuronal NIH3T3 or CHO cells. Finally, in chronically scrapie (PrPSc)-infected cells, ROS increased more than twofold while proteasome activity was decreased compared to control cells. Although this could be a direct effect of PrPSc, it is also possible that, since PrPC specifically prevents pathological protein aggregation in neuronal cells, partial loss of PrPC itself increases PrPSc aggregation.

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Section: Introductionmentioning

confidence: 99%

Cellular prion protein (PrPC) protects neuronal cells from the effect of huntingtin aggregation

Lee

Panzera

Rogawski

et al. 2007

Journal of Cell Science

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“…A proposed role for PrP is metal ion homeostasis (Brown, 2002;Watt and Hooper, 2003) because it binds copper avidly although its functional consequences, if any, are unclear (Davies and Brown, 2008). Other proposed roles for PrP include protection from oxidative stress (Brown, 2002;Krebs et al, 2007), although this is contentious (Hutter et al, 2003;Jones et al, 2005), and signal transduction (Rieger et al, 1997;Chiarini et al, 2002). In the brain, PrP particularly localizes to synaptic membranes (Herms et al, 1999;Fournier et al, 2000), suggesting a role in neurotransmission.…”

Section: Introductionmentioning

confidence: 99%

Alterations in Ca²⁺-Buffering in Prion-Null Mice: Association with Reduced Afterhyperpolarizations in CA1 Hippocampal Neurons

Powell¹,

Toescu²,

Collinge³

et al. 2008

J. Neurosci.

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“…Independently of the impact of Cu/ZnSOD activity in ALS, we observed no significant changes in SOD activity by deletion of Prp, so we conclude like others 32 that Prp does not possess direct SOD activity or SOD regulating potency.…”

Section: G93amentioning

confidence: 53%

Neuroprotective Function of Cellular Prion Protein in a Mouse Model of Amyotrophic Lateral Sclerosis

Steinacker

Hawlik

Lehnert

et al. 2010

The American Journal of Pathology

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Transgenic mice expressing human mutated superoxide dismutase 1 (SOD1) linked to familial forms of amyotrophic lateral sclerosis are frequently used as a disease model. We used the SOD1 G93A mouse in a crossbreeding strategy to study the function of physiological prion protein (Prp). SOD1 G93APrp؊/؊ mice exhibited a significantly reduced life span, and an earlier onset and accelerated progression of disease, as compared with SOD1 G93APrp؉/؉ mice. Additionally, during disease progression, SOD1 G93APrp؊/؊ mice showed impaired rotarod performance, lower body weight, and reduced muscle strength. Histologically, SOD1 G93APrp؊/؊ mice showed reduced numbers of spinal cord motor neurons and extended areas occupied by large vacuoles early in the course of the disease. Analysis of spinal cord homogenates revealed no differences in SOD1 activity. Using an unbiased proteomic approach, a marked reduction of glial fibrillary acidic protein and enhanced levels of collapsing response mediator protein 2 and creatine kinase were detected in SOD1 G93A Prp؊/؊ versus SOD1 G93A mice. In the course of disease , Bcl-2 decreases , nuclear factor-B increases , and Akt is activated , but these changes were largely unaffected by Prp expression. Exclusively in double-transgenic mice , we detected a significant increase in extracellular signal-regulated kinase 2 activation at clinical onset. We propose that Prp has a beneficial role in the SOD1 G93A amyotrophic lateral sclerosis mouse model by influencing neuronal and/or glial factors involved in antioxidative defense , rather than anti- Amyotrophic lateral sclerosis is characterized by rapid degeneration of motor neurons in the spinal cord, brain stem, and cortical Betz cells. As a result, focal muscle wasting, weakness, and spasticity develop focally. These symptoms ultimately lead to global paralysis. Patients usually die due to respiratory failure within 3 years of symptom onset. The causes of ALS are diverse; 10 to 15% of cases are familial with autosomal dominant inheritance, and 20% of these are related to point mutations in the gene encoding Cu/Zn superoxide dismutase 1 (SOD1). SOD1 is a ubiquitously expressed homodimeric protein that catalyzes the reaction of O 2 Ϫ to O 2 and H 2 O 2 , which is then further metabolized by glutathione peroxidase. Mice overexpressing human mutated SOD1 (muSOD1) linked to ALS, develop disease resembling ALS in humans by a toxic gain of function.2 Several properties of muSOD1 were proposed to contribute to toxic gain of function, including enhanced peroxidase activity and formation of peroxynitrite, changes in copper and zinc binding, and aggregation of the enzyme. ALS progression is accompanied by oxidative stress processes, glutamate-induced excitotoxicity, cytoskeletal abnormalities, inflammatory processes, and toxicity via extracellular muSOD1.2,3 The apoptotic cascade is activated in the ALS model, shown by sequential activation of caspase-1 and Ϫ3.4 Interestingly, Bcl-2 overexpression had a neuroprotective effect and, like intrathecal administrati...

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Recombinant prion protein does not possess SOD-1 activity

Cited by 77 publications

References 33 publications

Cellular prion protein (PrPC) protects neuronal cells from the effect of huntingtin aggregation

Cellular prion protein (PrPC) protects neuronal cells from the effect of huntingtin aggregation

Alterations in Ca²⁺-Buffering in Prion-Null Mice: Association with Reduced Afterhyperpolarizations in CA1 Hippocampal Neurons

Neuroprotective Function of Cellular Prion Protein in a Mouse Model of Amyotrophic Lateral Sclerosis

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Recombinant prion protein does not possess SOD-1 activity

Cited by 77 publications

References 33 publications

Cellular prion protein (PrPC) protects neuronal cells from the effect of huntingtin aggregation

Cellular prion protein (PrPC) protects neuronal cells from the effect of huntingtin aggregation

Alterations in Ca2+-Buffering in Prion-Null Mice: Association with Reduced Afterhyperpolarizations in CA1 Hippocampal Neurons

Neuroprotective Function of Cellular Prion Protein in a Mouse Model of Amyotrophic Lateral Sclerosis

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Alterations in Ca²⁺-Buffering in Prion-Null Mice: Association with Reduced Afterhyperpolarizations in CA1 Hippocampal Neurons