In Vivo Phosphorylation and Cellular Transport of Mutant and WT Prion Proteins in Living Neurons

Selected proteins undergo polarized sorting in neurons to selected synapses. This process is affected by certain diseases of the central nervous system. Almost all proteins involved in Alzheimer's disease (AD) and specifically those required for amyloid ?ü-peptide (A?ü)
generation are targeted either to axons or the somatodendritic compartment (Capell et al., 2002; Haass et al., 1995a; Haass et al., 1994; Haass et al., 1995b). Correct sorting of these proteins affects A?ü generation at least in familial AD. We now searched for transport signals
within PrP, which may be required for polarized sorting and may be affected by pathogenic mutations. We identified a dominant signal for basolateral transport within the hydrophobic putative trans-membrane domain (HD domain) of PrP. This domain is lacking in the PrP
homologue Doppel (Dpl), which as a consequence is targeted to the opposite surface. When the PrP HD-domain was inserted into Dpl, the chimeric protein underwent basolateral sorting.<p>
Conversely, when the HD domain was deleted in PrP it was targeted apically. Strikingly, basolateral transport was blocked by a pathogenic PrP mutant within the HD domain. Co-expression of Dpl and PrP leads to an aberrant sorting of PrP. Presumably this is due to an interaction of Dpl with PrP, which may hide the sorting signal within the HD domain.
Currently we are investigating the influence of ADAM proteases on potential shedding of PrP (see (Wild-Bode et al., 2006)).<p>
The trafficking data are summarized in Figure 1 and published (Uelhoff et al., 2005).