Prion protein inhibits fast axonal transport through a mechanism involving casein kinase 2.

Emiliano Zamponi,Gustavo F Pigino,Mary J Ladu,Pablo R Helguera,Alfredo Lorenzo,Yuyu Song,Gerardo A Morfini,Scott T Brady,Lisa M Jungbauer,Gabriel Cataldi,Hector Hugo Caicedo,Mariano Bisbal,Fiamma Buratti,Jiyan Ma

doi:10.1371/journal.pone.0188340

Abstract

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.

Highlights

Prion diseases include a number of fatal sporadic, familial and infectious neuropathies affecting humans and other mammals [1]
Various neurotoxic effects were associated with intracellular accumulation of wild type, non-infectious prion protein (PrP)-FL [5], but whether PrP-FL could directly affect fast axonal transport (FAT) was not previously tested
Experimental data documented toxic effects of a PrP peptide encompassing residues 106–126 on primary hippocampal, cortical and cerebellar cultured neurons [52,53,54,55,56,57]. These findings prompted us to evaluate whether the central domain (CD) domain may mediate the toxic effect of PrP-FL on FAT

Summary

Introduction

Prion diseases include a number of fatal sporadic, familial and infectious neuropathies affecting humans and other mammals [1]. As observed in most adult-onset neurodegenerative diseases [2], neurons affected in prion diseases follow a dying back pattern of degeneration, where synaptic dysfunction and loss of neuritic connectivity represent early pathogenic events that long precede cell death [3, 4]. Toxic effects of prion protein (PrP) have been shown in various cellular and animal models [5,6,7]. Institutes of Health NS066942A and NS096642 (to GM), R01-NS023868 and R01-NS041170 (to STB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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