Macroautophagy, often referred to as autophagy is a highly conserved mechanism by which mammalian cells survive nutrient deprivation through digestion and recycling of intracellular organelles. A growing body of evidence indicates that autophagy also supports neuronal survival removing altered organelles or misfolded proteins from the cytoplasm; indeed, failure of autophagic clearance of amyloidogenic proteins has been described in association with several neurodegenerative disorders. Our research was headed to challenge pharmacological strategies against the neurotoxicity of amyloidogenic peptides through the modulation of autophagy. We have induced neurotoxicity in mesencephalic cell line A1 using the amyloidogenic c-terminal fragment of prion protein (PrP90-231) whose neurotoxicity in vitro is associated with its propensity to be internalized and form cytoplasmic insoluble and protease-resistant aggregates. PrP90-231 induced A1 cell death and stimulated the increase in number and size of acidic vesicles. PrP90-231 increased the expression and cytosolic distribution of hydrolytic enzyme cathepsin D (CatD) indicating that intracellular aggregation of the peptide impairs lysosomal integrity. Analysis of protein expression showed that PrP90-231 increased the expression of autophagic markers such as LC3II and beclin1; moreover, by electron microscopy, we observed that PrP90-231 condensates within autophagic vacuoles whose number is significantly increases after cell exposure to the peptide. Stimulation of autophagy, by trophic factor deprivation or through the pharmacological blockade of mTOR kinase, reduced significantly A1 cell death and the amount of internalized PrP90-231. Altogether, these data indicates that PrP90-231 internalization produces a defensive response in A1 cells in terms of induction of autophagy and that enhancing such process could represents a promising goal of neuroprotective pharmacological strategies.
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|Titolo:||ACTIVATION OF AUTOPHAGY PATHWAY AS NEUROPROTECTIVE MECHANISM AGAINST AMYLOIDOGENIC PRION PEPTIDE|
|Data di pubblicazione:||2015|
|Appare nelle tipologie:||04.02 - Abstract in atti di convegno|