Mutant PrP Suppresses Glutamatergic Neurotransmission in Cerebellar Granule Neurons by Impairing Membrane Delivery of VGCC α2δ-1 Subunit

Abstract

SummaryHow mutant prion protein (PrP) leads to neurological dysfunction in genetic prion diseases is unknown. Tg(PG14) mice synthesize a misfolded mutant PrP which is partially retained in the neuronal endoplasmic reticulum (ER). As these mice age, they develop ataxia and massive degeneration of cerebellar granule neurons (CGNs). Here, we report that motor behavioral deficits in Tg(PG14) mice emerge before neurodegeneration and are associated with defective glutamate exocytosis from granule neurons due to impaired calcium dynamics. We found that mutant PrP interacts with the voltage-gated calcium channel α2δ-1 subunit, which promotes the anterograde trafficking of the channel. Owing to ER retention of mutant PrP, α2δ-1 accumulates intracellularly, impairing delivery of the channel complex to the cell surface. Thus, mutant PrP disrupts cerebellar glutamatergic neurotransmission by reducing the number of functional channels in CGNs. These results link intracellular PrP retention to synaptic dysfunction, indicating new modalities of neurotoxicity and potential therapeutic strategies.

Early infantile epileptic encephalopathy associated with a high voltage gated calcium channelopathy

“…α 2 δ2-L1040P is unable to reproduce the most common effects of α 2 δ2-WT: an increase in whole cell amplitude and acceleration of inactivation 22 23. Since α 2 δ increases hVGCC currents both via effects on channel gating and surface expression,6 24 25 the α 2 δ2-L1040P mutant appears deficient in performing one or both of these essential functions. Prolonged channel opening during depolarisation, associated with slow inactivation, could partly underlie the epileptic phenotype; low current amplitude would add to the development of an aberrant calcium signalling pattern.…”

“…Prolonged channel opening during depolarisation, associated with slow inactivation, could partly underlie the epileptic phenotype; low current amplitude would add to the development of an aberrant calcium signalling pattern. Furthermore, lack or dysfunction of α 2 δ2 is expected to affect synaptogenesis and spatio-temporal calcium signalling,13 25 aggravating the pathology. Our clinical data and the results of the electrophysiological studies are in agreement with the spike wave seizures reported in mice carrying a spontaneous mutation in α 2 δ2 (ducky alleles) associated with an aberrant α 2 δ2 protein 26–29.…”

The biological function of the cellular prion protein: an update

“…Also, PrP C and a mutant PrP C version that is linked to a genetic prion disease have been shown to co-immunoprecipitate with the auxiliary subunit α2δ-1 of VGCCs in transgenic mice [78]. Mutant PrP C affected α2δ-1 trafficking and function at the synapses.…”

Alternative fates of newly formed PrPSc upon prion conversion on the plasma membrane

“…A major gap exists in our understanding of how conversion of PrP C to PrP Sc causes neuronal dysfunction and death. Various mechanisms have been proposed including synaptic impairment (Senatore et al, 2012), ubiquitin-proteasome system (UPS) dysfunction (Kristiansen et al, 2007), endoplasmic reticulum (ER) stress (Hetz et al, 2003;Rane et al, 2008), toxicity due to the presence of PrP species in the cytosol (Chakrabarti and Hegde, 2009;Kristiansen et al, 2005;Ma et al, 2002), and unfolded protein response induction and translational arrest (Moreno et al, 2012). To assess the contribution of these mechanisms to prion-induced toxicity, it is essential to know the exact cellular trafficking pathways of PrP Sc .…”