Prions: health scare and biological challenge

Aguzzi, Adriano; Montrasio, Fabio; Kaeser, Pascal S.

doi:10.1038/35052063

Cited by 139 publications

(91 citation statements)

References 86 publications

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“…The prion protein (PrP) is the causative agent of the transmissible spongiform encephalopathies (TSEs) that include CreutzfeldtJakob disease (CJD), Gerstmann-Scheinker-Straussler (GSS) disease, kuru and fatal familial insomnia in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep (4). In these diseases, the normal cellular form of PrP (PrP C ) undergoes a conformational change to the infectious form, PrP Sc .…”

mentioning

confidence: 99%

Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein

Parkin

Watt²,

Hussain³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

255

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Proteolytic processing of the amyloid precursor protein (APP) by ␤-secretase, ␤-site APP cleaving enzyme (BACE1), is the initial step in the production of the amyloid ␤ (A␤) peptide, which is involved in the pathogenesis of Alzheimer's disease. The normal cellular function of the prion protein (PrP C ), the causative agent of the transmissible spongiform encephalopathies such as CreutzfeldtJakob disease in humans, remains enigmatic. Because both APP and PrP C are subject to proteolytic processing by the same zinc metalloproteases, we tested the involvement of PrP C in the proteolytic processing of APP. Cellular overexpression of PrP C inhibited the ␤-secretase cleavage of APP and reduced A␤ formation. Conversely, depletion of PrP C in mouse N2a cells by siRNA led to an increase in A␤ peptides secreted into the medium. In the brains of PrP knockout mice and in the brains from two strains of scrapieinfected mice, A␤ levels were significantly increased. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases failed to inhibit the ␤-secretase cleavage of APP. Using constructs of PrP, we show that this regulatory effect of PrP C on the ␤-secretase cleavage of APP required the localization of PrP C to cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic region of PrP C via interaction with glycosaminoglycans. In conclusion, this is a mechanism by which the cellular production of the neurotoxic A␤ is regulated by PrP C and may have implications for both Alzheimer's and prion diseases.lipid raft ͉ proteolysis ͉ scrapie ͉ glycosaminoglycan A lzheimer's disease (AD) is characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles within the afflicted brain. The major constituents of senile plaques are the amyloid ␤ (A␤) peptides, which are derived from the proteolytic processing of the amyloid precursor protein (APP) (1). In the amyloidogenic pathway, ␤-secretase cleavage of APP yields a soluble N-terminal fragment sAPP␤, along with a short membrane-bound C-terminal fragment that is subsequently cleaved by ␥-secretase to release the A␤ peptides. In the alternative, nonamyloidogenic pathway, ␣-secretase cleaves APP within the A␤ sequence, thus precluding the formation of A␤, and releases a soluble N-terminal fragment sAPP␣. The transmembrane aspartyl protease, ␤-site APP cleaving enzyme (BACE1), has been identified as ␤-secretase (2), members of the ADAM (a disintegrin and metalloprotease) family, particularly ADAM10 and ADAM17, are responsible for ␣-secretase cleavage (3), while a complex of at least four proteins, the presenilins, nicastrin, Aph-1, and Pen-2, constitutes the ␥-secretase (2).The prion protein (PrP) is the causative agent of the transmissible spongiform encephalopathies (TSEs) that include CreutzfeldtJakob disease (CJD), Gerstmann-Scheinker-Straussler (GSS) disease, kuru and fatal familial insomnia in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep (4). In these diseases, the normal ce...

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mentioning

confidence: 99%

Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein

Parkin

Watt²,

Hussain³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

255

View full text Add to dashboard Cite

show abstract

“…Prion diseases are transmissible, fatal neurodegenerative diseases affecting animals and humans (1). The prototypical human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD), is thought to originate in the CNS, and no significant accumulation of the infectious agent (the prion) is found in extracerebral compartments.…”

mentioning

confidence: 99%

Peripheral prion pursuit

Aguzzi¹

2001

J. Clin. Invest.

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“…PrP Sc is generated through a conformational transformation of PrP C and represents the major component of infectious prions (reviewed in Refs. [1][2][3][4]. PrP 1 is post-translationally modified by the attachment of two N-linked complex carbohydrate moieties (Asn 180 and Asn 196 ) (5-7) and a glycosylphosphatidylinositol (GPI) anchor at serine 231 (8) as well as by the formation of a disulfide bond between Cys 178 and Cys 213 .…”

mentioning

confidence: 99%

“…It has been found that the only specific marker for ER import of PrP is a cleaved N-terminal signal sequence (10). 2 Misfolding of PrP C in the cytosol or in the ER can induce neurodegeneration in the absence of PrP Sc . Neurotoxic properties of cytosolic PrP aggregates were observed after proteasomal inhibition in cultured cells or after the forced expression of cytosolic PrP in transgenic mice (15).…”

mentioning

confidence: 99%

Post-translational Import of the Prion Protein into the Endoplasmic Reticulum Interferes with Cell Viability

Heller

Winklhofer

Heske

et al. 2003

Journal of Biological Chemistry

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Aberrant folding of the mammalian prion protein (PrP) is linked to prion diseases in humans and animals. We show that during post-translational targeting of PrP to the endoplasmic reticulum (ER) the putative transmembrane domain induces misfolding of PrP in the cytosol and interferes with its import into the ER. Unglycosylated and misfolded PrP with an uncleaved N-terminal signal sequence associates with ER membranes, and, moreover, decreases cell viability. PrP expressed in the cytosol, lacking the N-terminal ER targeting sequence, also adopts a misfolded conformation; however, this has no adverse effect on cell growth. PrP processing, productive ER import, and cellular viability can be restored either by deleting the putative transmembrane domain or by using a N-terminal signal sequence specific for co-translational ER import. Our study reveals that the putative transmembrane domain features in the formation of misfolded PrP conformers and indicates that post-translational targeting of PrP to the ER can decrease cell viability.Prion diseases in humans and animals are characterized by the accumulation of PrP Sc , a partially protease-resistant isoform of the cellular prion protein PrP C . PrP Sc is generated through a conformational transformation of PrP C and represents the major component of infectious prions (reviewed in Refs. 1-4). PrP 1 is post-translationally modified by the attachment of two N-linked complex carbohydrate moieties (Asn 180 and Asn 196 ) (5-7) and a glycosylphosphatidylinositol (GPI) anchor at serine 231 (8) as well as by the formation of a disulfide bond between Cys 178 and Cys 213 . Studies with recombinant PrP purified from bacteria revealed that the formation of the disulfide bond is essential for the native folding of PrP (9).The co-and post-translational modifications of PrP C are initiated with the cleavage of the N-terminal signal peptide (aa 1-22) and the transfer of core glycans, whereas the nascent chain is still associated with the translocon. Shortly after the protein is fully translocated, the GPI anchor is attached to the acceptor amino acid close to the C terminus. The final maturation of PrP C includes the processing of the core glycans into complex-type glycans by a series of enzymatic reactions in the endoplasmic reticulum (ER) and Golgi compartment. Posttranslational modifications, like N-linked glycosylation and GPI anchor attachment, are often used as diagnostic markers to monitor efficient import into the ER. In the case of PrP, however, we and others have shown that PrP devoid of a GPI anchor remains mainly unglycosylated but is imported efficiently into the ER and transported through the secretory pathway (10 -14). It has been found that the only specific marker for ER import of PrP is a cleaved N-terminal signal sequence (10). 2 Misfolding of PrP C in the cytosol or in the ER can induce neurodegeneration in the absence of PrP Sc . Neurotoxic properties of cytosolic PrP aggregates were observed after proteasomal inhibition in cultured cells or after the forced expr...

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Prions: health scare and biological challenge

Cited by 139 publications

References 86 publications

Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein

Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein

Peripheral prion pursuit

Post-translational Import of the Prion Protein into the Endoplasmic Reticulum Interferes with Cell Viability

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