Figure 9. Dpl-mediated model of cerebellar neurodegeneration.

The model bears on the postulations as follows: (A) PrP and α₂M do not interact each other, therefore α₂M is physiologically regulated in the cerebellum; (B) in Prnp ^0/0 mice, α₂M is still under physiological regulation as in wild type situation; (C) in absence of PrP and in simultaneous presence of Dpl, α₂M is sequestered and deregulated, thus leading to cerebellar neurodegeneration. (D) PrP and Dpl are co-expressed, bind and antagonize each other depending on their stoichiometric ratio: on the left, PrP levels are higher than Dpl, PrP sequesters the entire amount of Dpl and thus prevents Dpl interaction with α₂M; on the right, Dpl expression is higher than PrP, and residual amounts of Dpl unbound to PrP are still capable of binding α₂M. (E) N-terminally truncated PrP binds with less affinity to Dpl, thus permitting it to bind α₂M. Mouse models are cited as follows: ZrchI Prnp ^0/0 [53]; Edimburgh Prnp ^-/- [54]; Rcm0 Prnp ^0/0 [3]; ZrchII Prnp ^0/0 [55]; Ngsk Prnp ^0/0 [6].