The scrapie prion protein is present in flotillin‐1‐positive vesicles in central‐ but not peripheral‐derived neuronal cell lines

Abstract

Transmissible prion diseases are fatal neurodegenerative diseases associated with the conversion of the normal host prion protein (PrP c) into an abnormal isoform (PrP Sc) that accumulates in brain. This pathology affects neurons of the central nervous system whereas no clear toxic effect has been reported for peripheral neurons. We examined the subcellular distribution of PrP c and PrP Sc in the scrapie-infected mouse neuronal cell lines GT1-7 and N2a, derived, respectively, from the central and peripheral nervous system. We observed that in both cell types, PrP c is present in the endocytic compartment, mainly in LAMP-1-positive late endosomes, but excluded from LYAAT-1-lysosomes. In contrast, PrP Sc was distributed differently in the two cell lines. In infected N2a, PrP Sc and PrP c had comparable distribution patterns. In infected GT1-7, PrP Sc is present in an additional vesicular compartment which is flotillin-1-positive. The level of expression of flotillin-1 is higher in GT1-7 than in N2a cells, but no difference is observed between infected and noninfected cells. In Alzheimer's disease patients, it has been reported that flotillin-1 is abundant in brain areas containing the beta-amyloid protein, which accumulates in endosomal vesicles in primary neurons. We propose that the flotillin compartment could store aggregated proteins and play a role in these neurodegenerative pathologies.

Spreading of prions from the immune to the peripheral nervous system: a potential implication of dendritic cells

“…Our system did not contain any microglial cells and could therefore have been protected from neurotoxicity. (b) Within the neurons of the CNS, PrP Sc was localized in two diVerent compartments: LAMP-1 and Xotillin1 vesicles, whereas in the PNS prions were only located in LAMP-1 vesicles (Pimpinelli et al 2005;Leblanc et al 2006). This supplementary compartment in the CNS could explain the lack of neurotoxicity in our system using peripheral neurons.…”

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

“…For the intracellular transduction of PrP c -STI1-mediated signaling, endocytosis of PrP c is required (Americo et al, 2007;Caetano et al, 2008). For this reason, a strong correlation between PrP c trafficking alterations and prion pathologies have been suggested in other studies (Borchelt et al, 1992;Kiachopoulos et al, 2004;Pimpinelli et al, 2005;Shyng et al, 1995). Lastly, a recent study has reported PrP c -independent functions of STI1 in cell proliferation (Arruda-Carvalho et al, 2007).…”

Les prions exploitent les communications neuro-immunitaires

“…Dans des neurones du SNP et du SNC, la PrP c et la PrP Sc sont localisées dans des endosomes tardifs exprimant LAMP-1 (lysosomal-associated membrane protein 1). La PrP Sc dans le SNC est aussi localisée dans des vésicules exprimant la flotilline-1, une protéine associée aux radeaux lipidiques [34]. Ce compartiment supplémentaire dans les neurones centraux où des protéines peuvent être stockées expliquerait la différence de sensibilité aux prions des deux types de neurones [35].…”