, 2010). By comparing the effect of HC-deleted and full-length molecules on α2δ-1 trafficking and calcium dynamics, we provided evidence Icotinib that VGCC dysfunction depends on intracellular retention of mutant PrP. This, and the fact that PrP interacts physically with the α2δ-1 subunit, suggests

a mechanism whereby interaction between mutant PrP and α2δ-1 results in the latter being sequestered in secretory organelles, impairing correct assembly and delivery of the channel complex to synaptic sites. Although this can readily explain the low levels of VGCCs at presynaptic terminals, an indirect mechanism might also be involved. PrP may participate in cell signaling governing membrane protein transport (Málaga-Trillo et al., 2009) that could be altered by pathogenic

mutations. We did in fact find that cells expressing D177N PrP had an impairment in Rab11-dependent trafficking (Massignan et al., 2010), which could potentially affect the endocytic recycling of α2δ-1 (Tran-Van-Minh and Dolphin, 2010). Our analysis indicates that glutamatergic neurotransmission in Tg(PG14) mice is preferentially impaired in CGNs, in line with the selective expression of α2δ-1 by these cells in the Selleck Nintedanib cerebellum (Cole et al., 2005). However, α2δ-1 is also expressed by glutamatergic neurons in other brain regions (Cole et al., 2005). Therefore, there might be defects in α2δ-1 transport and neurotransmission in other neural systems, which could be responsible for additional

neurological signs. For example the deficit in spatial working memory in Tg(CJD) mice (Dossena et al., 2008) might depend on abnormal glutamatergic function in the hippocampus. Three different α2δ subunits are expressed in functionally distinct neurons of the brain, with Cytidine deaminase the α2δ-2 and α2δ-3 isoforms sharing, respectively, 55.6% and 30.3% sequence identity with α2δ-1 (Klugbauer et al., 1999). It will be interesting to see if PrP interacts with α2δ-2 and α2δ-3, and if their cellular trafficking is affected by mutant PrP, as with α2δ-1. It will also be important to see whether VGCC dynamics are perturbed in prion diseases acquired by infection. N-type VGCC function is impaired in prion-infected hypothalamic GT1-1 cells (Sandberg et al., 2004), but it is not clear whether this is due to deficient channel insertion in the plasma membrane. At an advanced stage of disease, Tg(PG14) mice show synaptic degeneration in the cerebellar molecular layer and apoptosis of granule neurons, raising the possibility that functional impairment of α2δ subunits resulting from sequestration by mutant PrP may eventually lead to synaptic disruption and neuron demise. Consistent with this, targeted deletion or spontaneous mutation of the mouse Cacna2d2 gene encoding α2δ-2, which is primarily present in Purkinje neurons, results in cerebellar ataxia with PC depletion and apoptosis of granule neurons ( Barclay et al., 2001 and Ivanov et al., 2004).