Prion diseases include a number of progressive neuropathies involving conformational changes in cellular prion protein (PrPc) that may be fatal sporadic, familial or infectious. Pathological evidence indicated that neurons affected in prion diseases follow a dying-back pattern of degeneration. However, specific cellular processes affected by PrPc that explain such a pattern have not yet been identified. Results from cell biological and pharmacological experiments in isolated squid axoplasm and primary cultured neurons reveal inhibition of fast axonal transport (FAT) as a novel toxic effect elicited by PrPc. Pharmacological, biochemical and cell biological experiments further indicate this toxic effect involves casein kinase 2 (CK2) activation, providing a molecular basis for the toxic effect of PrPc on FAT. CK2 was found to phosphorylate and inhibit light chain subunits of the major motor protein conventional kinesin. Collectively, these findings suggest CK2 as a novel therapeutic target to prevent the gradual loss of neuronal connectivity that characterizes prion diseases.

Recent studies suggest that Tyr-39 might play a critical role for both the normal function and the pathological dysfunction of α-synuclein (αS), an intrinsically disordered protein involved in Parkinson’s disease. We perform here a comparative analysis between the structural features of human αS and its Y39A, Y39F, and Y39L variants. By the combined application of site-directed mutagenesis, biophysical techniques, and enhanced sampling molecular simulations, we show that removing aromatic functionality at position 39 of monomeric αS leads to protein variants populating more compact conformations, conserving its disordered nature and secondary structure propensities. Contrasting with the subtle changes induced by mutations on the protein structure, removing aromaticity at position 39 impacts strongly on the interaction of αS with the potent amyloid inhibitor phthalocyanine tetrasulfonate (PcTS). Our findings further support the role of Tyr-39 in forming essential inter and intramolecular contacts that might have important repercussions for the function and the dysfunction of αS.