Prion Propagation, Its Neurotoxicity, and Protein Trafficking
Suehiro Sakaguchi and Keiji Uchiyama
from: Prions: Current Progress in Advanced Research (Second Edition) (Edited by: Akikazu Sakudo and Takashi Onodera). Caister Academic Press, U.K. (2019) Pages: 39-54.
Conformational conversion of the cellular prion protein, PrPC, into the abnormally folded isoform of prion protein, PrPSc, which leads to its accumulation or propagation, is a key pathogenic event in prion diseases which are a group of fatal neurodegenerative disorders. We recently reported that the VPS10P sorting receptor, sortilin, negatively regulates PrPSc accumulation in prion-infected neurons, by trafficking PrPC and PrPSc to lysosomes for degradation, and that PrPSc conversely stimulates lysosomal degradation of sortilin, thereby disrupting the sortilin-mediated degradation of PrPC and PrPSc. These results suggest a positive feedback amplification mechanism for PrPSc accumulation in prion-infected neurons. We also showed that prions could selectively impair post-Golgi vesicular trafficking well before mice became sick after infection, suggesting that the post-Golgi vesicular trafficking impairment could be an early pathogenic event in prion diseases. Here, we will discuss our current findings in detail read more ...