Selective degradation of prion protein aggregates via autolysososmal pathway by polyamine spermine

The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, Scotland, UK

Aggregation of misfolded proteins is a hallmark of many neurodegenerative disorders which are debilitating and largely untreatable. There are no therapies to date which can modify the progression of these diseases. Enhancing pathways responsible for clearance of misfolded proteins has emerged as a prime therapeutic strategy. In Prion diseases conformationally altered protein (PrPSc) aggregates deposit in the CNS and peripheral tissues, formed from the normal cell-surface glycoprotein PrPC. The prion mouse models display all the features common to many chronic neurodegenerative processes with early behavioural changes associated with synaptic dysfunction. Pathological changes of gliosis and protein deposition are apparent during early stages of disease and widespread death of neurones in later stages of disease. Using prion disease as a model for neurodegeneration we aim to understand the role of cellular recycling pathway, autophagy, in the selective clearance of prion aggregates. Using in house in vitro and in vivo models for the disease we are investigating if enhancing the autophagic flux with spermine, a polyamine, can restore the neuronal health during prion disease. Our results indicate that 5μM of spermine can efficiently clear PrPSc aggregates from the SMB.s15 cells within 72 hours of treatment. We have further observed a significant increase in the number of autophagosomes which correlates well with the decline in PrPSc accumulation by 72hrs. Furthermore on spermine treatment we see modulation of acetylated core histone proteins, proteins involved in pro-autophagic response, prion disease and neurotoxicity.  We conclude that spermine and the pathways affected by spermine could be a novel therapeutic target for the diseases with protein aggregates.

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Funded by: BBSRC