Cytosolic PrP Induces Apoptosis of Cell by Disrupting Microtubule Assembly

Abstract

Prion protein (PrP) is able to bind with tubulin and to interfere with the formation of microtubule. To investigate the influence of accumulation of cytosolic PrP in cytoplasm on microtubule, plasmid pcDNA3.1-PrP23-230 expressing human PrP23-230 was introduced into HeLa cells. Immunoprecipitation assays identified the molecular interaction between cytosolic PrP and cellular tubulin. Confocal microscopy showed the co-localization of the expressed cytosolic PrP with tubulin in cytoplasm. Immunofluorescent assays of tubulin illustrated remarkable disruption of microtubular structures in the cells accumulated with cytosolic PrP. Meanwhile, the expressed cytosolic PrP significantly reduced cell viability and induced cell apoptosis. The amounts of microtubule protein in the cells expressing cytosolic PrP were decreased. Moreover, the levels of endogenous tubulin in the brain tissues of scrapie-infected hamsters were significantly lower than that of normal one. It highlights a close linkage between disruption of microtubule framework and cell death caused by abnormal presence of cellular PrP in cytoplasm. The association of apoptosis with microtubule-disrupting activity caused by cytosolic PrP may further provide insight into the unresolved biological function of PrP in the neurons.

Pathogenic Mechanisms of the Prion Protein Gene Mutations: A Review and Speculative Hypotheses for Pathogenic Potential of the Pro39Leu Mutation in the Associated FTD-Like Phenotype

“…These mutations generally decrease the ability of tau to bind microtubules, increasing its propensity to form abnormal cytotoxic fibers and compromising the ability of the cell to properly regulate microtubule dynamics. Additional evidence supports the idea that destabilization of the microtubule network may be a primary factor in neurotoxicity induced by PrP Sc [78][79][80][81]. Moreover, an induction of tau hyperphosphorylation by misfolded PrP and a direct interaction between PrP and tau have been demonstrated [82].…”

Recruitment of cellular prion protein to mitochondrial raft-like microdomains contributes to apoptosis execution

“…In this regard, our findings prompted us to hypothesize two levels of regulation of cell apoptosis by PrP C : on microtubules, where an early interaction of PrP C with tubulin can alter microtubule framework integrity (Li et al , 2011), and, later, on the mitochondrial membrane, where it interacts with raft-like microdomains. Finally, since PrP C raft-mediated trafficking appears to strictly depend upon apoptotic triggering, we can also suggest a reappraisal of the previously hypothesized formation of PrP Sc within acidic compartments.…”

Remarkable Reduction of MAP2 in the Brains of Scrapie-Infected Rodents and Human Prion Disease Possibly Correlated with the Increase of Calpain

“…Many previously studies have repeatedly identified that the levels of tubulin decreased in CNS tissues of naturally occurred or experimental human and animal TSEs [15], [16], [17]. Our previous studies have demonstrated that the CJD-associated PrPs can disrupt the cellular microtubule structure through different pathways [18].…”