Cell type-specific neuroprotective activity of untranslocated prion protein.
BACKGROUND
A key pathogenic role in prion diseases was proposed for a cytosolic form of the prion protein (PrP). However, it is not clear how cytosolic PrP localization influences neuronal viability, with either cytotoxic or anti-apoptotic effects reported in different studies. The cellular mechanism by which PrP is delivered to the cytosol of neurons is also debated, and either retrograde transport from the endoplasmic reticulum or inefficient translocation during biosynthesis has been proposed. We investigated cytosolic PrP biogenesis and effect on cell viability in primary neuronal cultures from different mouse brain regions.


RESULTS
Mild proteasome inhibition induced accumulation of an untranslocated form of cytosolic PrP in cortical and hippocampal cells, but not in cerebellar granules. A cyclopeptolide that interferes with the correct insertion of the PrP signal sequence into the translocon increased the amount of untranslocated PrP in cortical and hippocampal cells, and induced its synthesis in cerebellar neurons. Untranslocated PrP boosted the resistance of cortical and hippocampal neurons to apoptotic insults but had no effect on cerebellar cells.


CONCLUSIONS
These results indicate cell type-dependent differences in the efficiency of PrP translocation, and argue that cytosolic PrP targeting might serve a physiological neuroprotective function.
Dulbecco Telethon Institute, Milan, Italy.
Elena
E
Restelli
Luana
L
Fioriti
Susanna
S
Mantovani
Simona
S
Airaghi
Gianluigi
G
Forloni
Roberto
R
Chiesa
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents; D011328:Prions / Q000502:physiology*; D021381:Protein Transport; D019311:Staurosporine / Q000494:pharmacology
D018696:Neuroprotective Agents; D011328:Prions; D019311:Staurosporine