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New papers support involvement of metals & oxidative str

Kathy

Well-known member
New papers support role of transitional metals, oxidative stress and loss of normal PrPC function, as causal to prion disorders.

Neurotoxicology. 2006 Jun 18; [Epub ahead of print]

Interaction of metals with prion protein: Possible role of divalent cations in the pathogenesis of prion diseases.

Choi CJ, Kanthasamy A, Anantharam V, Kanthasamy AG

Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, 2062 Veterinary Medicine Building, Ames, IA 50011-1250, USA.

Prion diseases are fatal neurodegenerative disorders that affect both humans and animals. The rapid clinical progression, change in protein conformation, cross-species transmission and massive neuronal degeneration are some key features of this devastating degenerative condition. Although the etiology is unknown, aberrant processing of cellular prion proteins is well established in the pathogenesis of prion diseases. Normal cellular prion protein (PrP(c)) is highly conserved in mammals and expressed predominantly in the brain. Nevertheless, the exact function of the normal prion protein in the CNS has not been fully elucidated. Prion proteins may function as a metal binding protein because divalent cations such as copper, zinc and manganese can bind to octapeptide repeat sequences in the N-terminus of PrP(c). Since the binding of these metals to the octapeptide has been proposed to influence both structural and functional properties of prion proteins, alterations in transition metal levels can alter the course of the disease. Furthermore, cellular antioxidant capacity is significantly compromised due to conversion of the normal prion protein (PrP(c)) to an abnormal scrapie prion (PrP(sc)) protein, suggesting that oxidative stress may play a role in the neurodegenerative process of prion diseases. The combination of imbalances in cellular transition metals and increased oxidative stress could further exacerbate the neurotoxic effect of PrP(sc). This review includes an overview of the structure and function of prion proteins, followed by the role of metals such as copper, manganese and iron in the physiological function of the PrP(c), and the possible role of transition metals in the pathogenesis of the prion disease.

PMID: 16860868


J Biol Chem. 2006 Jul 27;

Overstimulation of PrPC signaling pathways by prion peptide 106-126 causes oxidative injury of bioaminergic neuronal cells.

Pietri M, Caprini A, Mouillet-Richard S, Pradines E, Ermonval M,
Grassi J, Kellermann O, Schneider B.

CNRS, Institut Andre Lwoff - CNRS FRE 2937, Villejuif 94800.

Transmissible Spongiform Encephalopathies, also called prion diseases, are characterized by neuronal loss linked to the accumulation of PrPSc, a pathologic variant of the cellular prion protein (PrPC). Although the molecular and cellular bases of PrPSc-induced neuropathogenesis are not yet fully understood, increasing evidence supports the view that PrPSc accumulation interferes with PrPC normal function(s) in neurons. In the present work, we exploit the properties of PrP-(106-126), a synthetic peptide encompassing residues 106-126 of PrP, to investigate into the mechanisms sustaining prion-associated neuronal damage. This peptide shares many physicochemical properties with PrPSc and is neurotoxic in vitro and in vivo. We examined the impact of PrP-(106-126) exposure on 1C11 neuroepithelial cells, their neuronal progenies and GT1-7 hypothalamic cells. This peptide triggers ROS overflow, MAPKs (ERK1/2) and SAPKs (p38 and JNK1/2) sustained activation, and apoptotic signals in 1C11-derived serotonergic and noradrenergic neuronal cells, while having no effect on 1C11 precursor and GT1-7 cells. The neurotoxic action of PrP-(106-126) relies on cell surface expression of PrPC, recruitment of a PrPC-Caveolin-Fyn signaling platform, and overstimulation of NADPH-oxidase activity. Altogether, these findings provide actual evidence that PrP-(106-126)-induced neuronal injury is caused by an amplification of PrPC-associated signaling responses, which notably promotes oxidative stress conditions. Distorsion of PrPC signaling in neuronal cells could hence represent a causal event in TSE pathogenesis.
PMID: 16864581
 

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