Genetic prion diseases: a study of the impact of the mutant prion protein on spine morphology and synaptic function

Prion diseases are fatal neurodegenerative disorders of humans and other mammals which can arise sporadically, be genetically inherited or acquired through infection. The key event in prion diseases is the conversion of the normal prion protein (PrPC) into a conformationally altered isoform (scrapie isoform, PrPSc) that accumulates in the central nervous system of affected individuals in a detergent-insoluble and protease-resistant form that is the main constituent of an unusual type of infectious particle (prion). Evidence is emerging that neuronal loss in inherited prion diseases is preceded by synaptic dysfunctions. We propose to clarify the mechanisms by which abnormal PrP affects normal synaptic activity, with the aim of devising effective strategies for early treatment. We have recently demonstrated that mutant PrP is retained in the endoplasmic reticulum where it interacts with several ion channels subunits, thus impairing their delivery to the cell surface and impacting synaptic transmission (Neuron 74:300-313, 2012). Given PrP has been described to interact also with glutamate receptors of both AMPA and NMDA types, we aimed to explore the possibility that mutant PrP may also impact the delivery of these receptors, thus also affecting postsynaptic function. We started to address this possibility through confocal analysis and electrophysiological recordings, using primary hippocampal neurons transfected with plasmids expressing mutant prion proteins. Preliminary results showed that exogenous expression of mutant prion proteins results in a decrease in the formation of mushroom spines and an increase in filopodia-like spines. These morphological changes are accompanied by functional alterations of synaptic transmission and by changes in glutamatergic receptors subunit distribution, thus indicating that mutant prion protein affects synaptic maturation and function. .