Study on the toxic mechanism of prion protein peptide 106–126 in neuronal and non neuronal cells

The inherited prion diseases such as Gerstmann-Sträussler-Scheinker syndrome (GSS) are linked to point mutations in the gene coding for the cellular isoform of the prion protein (PrPC). One particular point mutation A117V (Ala117 → Val) is linked to a variable pathology that usually includes deposition of neurofibrillary tangles. A prion protein peptide carrying this point mutation [PrP106-126(117V)] was generated and compared with a peptide based on the normal human sequence [PrP106-126(117A)]. The inclusion of this point mutation increased the toxicity of PrP106-126 which could be linked to an increased β-sheet content. An assay of microtubule formation in the presence of tau indicated that PrP106-126 decreased the rate of microtubule formation that could be related to the displacement of tau. PrP106-126 carrying the 117 mutation was more efficient at inhibiting microtubule formation. These results suggest a possible mechanism of toxicity for protein carrying this mutation via destabilization of the cytoskeleton and deposition of tau in filaments, as observed in GSS.

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Cellular prion protein suppressess the apoptotic cell death by mediating the intracellular H2O2 in primary culture and immortalized neuronal cells

Prions ◽

10.1007/4-431-29402-3_30 ◽

2006 ◽

pp. 205-205

Author(s):

Izuru Nakamura ◽

Takuya Nishimura ◽

Keiichi Saeki ◽

Yoshitsugu Matsumoto ◽

Takashi Onodera

Keyword(s):

Cell Death ◽

Primary Culture ◽

Prion Protein ◽

Apoptotic Cell ◽

Neuronal Cells ◽

Apoptotic Cell Death ◽

Cellular Prion Protein

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Prion protein-overexpressing cells show altered response to a neurotoxic prion protein peptide

Journal of Neuroscience Research ◽

10.1002/(sici)1097-4547(19981101)54:3<331::aid-jnr4>3.0.co;2-k ◽

1998 ◽

Vol 54 (3) ◽

pp. 331-340 ◽

Cited By ~ 24

Author(s):

David R. Brown

Keyword(s):

Prion Protein ◽

Altered Response ◽

Prion Protein Peptide

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Uptake and Neuritic Transport of Scrapie Prion Protein Coincident with Infection of Neuronal Cells

Journal of Neuroscience ◽

10.1523/jneurosci.0653-05.2005 ◽

2005 ◽

Vol 25 (21) ◽

pp. 5207-5216 ◽

Cited By ~ 104

Author(s):

A. C. Magalhaes

Keyword(s):

Prion Protein ◽

Neuronal Cells

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The low-density lipoprotein receptor-related protein 1 (LRP1) mediates the endocytosis of the cellular prion protein

Biochemical Journal ◽

10.1042/bj20061736 ◽

2007 ◽

Vol 402 (1) ◽

pp. 17-23 ◽

Cited By ~ 85

Author(s):

David R. Taylor ◽

Nigel M. Hooper

Keyword(s):

Prion Protein ◽

Low Density Lipoprotein ◽

Neuronal Cells ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Adaptor Protein ◽

Cellular Prion Protein ◽

Low Density ◽

Related Protein ◽

Density Lipoprotein Receptor

PrPC (cellular prion protein) is located at the surface of neuronal cells in detergent-insoluble lipid rafts, yet is internalized by clathrin-dependent endocytosis. As PrPC is glycosyl-phosphatidylinositol-anchored, it requires a transmembrane adaptor protein to connect it to the clathrin endocytosis machinery. Using receptor-associated protein and small interfering RNA against particular LDL (low-density lipoprotein) family members, in combination with immunofluorescence microscopy and surface biotinylation assays, we show that the transmembrane LRP1 (LDL receptor-related protein 1) is required for the Cu2+-mediated endocytosis of PrPC in neuronal cells. We show also that another LRP1 ligand that can cause neurodegenerative disease, the Alzheimer's amyloid precursor protein, does not modulate the endocytosis of PrPC.

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