Prions: Protein Aggregation and Infectious Diseases - Physiological ...
Prions: Protein Aggregation and Infectious Diseases - Physiological ...
Prions: Protein Aggregation and Infectious Diseases - Physiological ...
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1120 ADRIANO AGUZZI AND ANNA MARIA CALELLA<br />
FIG. 6. Toxicity mediated by abnormal topology or altered trafficking of PrP C . The normal cellular isoform of prion protein, PrP C (green coils),<br />
is synthesized, folded, <strong>and</strong> glycosylated in the endoplasmic reticulum (ER), where its glycosyl phosphatidylinositol (GPI) anchor is added, before<br />
further modification in the Golgi complex. Mature PrP C translocates to the outer leaflet of the plasma membrane. Instead, Ctm PrP <strong>and</strong> Ntm PrP are<br />
unusual transmembrane forms, generated in the ER, which have their COOH or NH 2 terminus in the ER lumen, respectively. It has been suggested<br />
that misfolded <strong>and</strong> aberrantly processed PrP (cyPrP <strong>and</strong> Ctm PrP, respectively) (orange coils), which would normally be degraded by the proteasomes<br />
through the ER-associated degradation (ERAD) pathway, aggregate in the cytoplasm <strong>and</strong> cause cell death. Putative proteasomal inhibition or<br />
malfunction during prion disease would contribute to this route of toxicity. Induction of ER stress by PrP Sc may lead to translocation of nascent<br />
PrP C molecules to the cytosol for proteasomal degradation as a way to alleviate the overloaded ER (pQC pathway). However, this mechanism of<br />
defense turns negative under chronic ER stress conditions, overwhelming the proteasome <strong>and</strong> leading to the cytosolic accumulation of potentially<br />
toxic PrP molecules (dashed lines).<br />
promised ER function. However, under chronic ER stress<br />
conditions, the proteasome may become overwhelmed,<br />
resulting in PrP accumulation in the cytosol. According to<br />
the study of Rane et al. (417), even a modest increase in<br />
PrP routing to pQC for prolonged periods of time causes<br />
clinical <strong>and</strong> histological neurodegenerative changes reminiscent,<br />
in some aspects, of those observed in prion<br />
diseases.<br />
Although ER stress in prion diseases is well documented<br />
(217), the relevance or even the existence of cy(PrP)<br />
continues to be rather controversial (142, 152). Furthermore,<br />
the transgenic mice with increased PrP translocation<br />
to the pQC pathway reported by Rane et al. (417) showed a<br />
relatively mild neurodegenerative phenotype that resembles<br />
only a subset of TSE pathology, <strong>and</strong> other cellular pathways<br />
Physiol Rev VOL 89 OCTOBER 2009 www.prv.org<br />
may also be contributing to prion-induced neurodegeneration<br />
(472). A role for dysfunction of the ubiquitin-proteasome<br />
system (UPS) in the pathogenesis of prion disease was<br />
also suggested: neuronal propagation of prions in the presence<br />
of mild proteasome impairment triggered a neurotoxic<br />
mechanism involving the intracellular formation of cytosolic<br />
PrP Sc aggresomes that, in turn, activated caspase-dependent<br />
neuronal apoptosis. A similar effect was also seen in vivo in<br />
brains of prion-infected mice (285). In a follow-up study, the<br />
same group reported that disease-associated prion protein<br />
specifically inhibited the proteolytic -subunits of the 26S<br />
proteasome. Upon challenge with recombinant prion <strong>and</strong><br />
other amyloidogenic proteins, only the prion protein in a<br />
nonnative -sheet conformation inhibited the 26S proteasome<br />
at stoichiometric concentrations. Furthermore, there