Current Molecular Medicine 2004, 4, 397-403 397 1566-5240/04 $45.00+.00 © 2004 Bentham Science Publishers Ltd. Molecular Mechanisms of Neurotoxicity of Pathological Prion Protein Joaquín Castilla 1 , Claudio Hetz 2,3 and Claudio Soto 1* 1 University of Texas Medical Branch, Galveston, TX77555, USA 2 Serono Pharmaceutical Research Institute, Geneva, Switzerland 3 Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile Abstract: Transmissible Spongiform Encephalopathies or prion related disorders are fatal and infectious neurodegenerative diseases characterized by extensive neuronal apoptosis and accumulation of a misfolded form of the cellular prion protein (PrP), denoted PrP Sc . Although the mechanism of neurodegeneration and the involvement of PrP Sc is far from clear, data indicates that neuronal apoptosis might be related to activation of several signaling pathways, including proteasome dysfunction, alterations in prion maturation pathway and endoplasmic reticulum (ER) stress. In this article we describe recent studies investigating the molecular mechanism of PrP Sc neurotoxicity. We propose a model in which the key step in the pathogenesis of prion disorders, independent on their etiology, is the alteration of ER-homeostasis due to drastic modifications of the physicochemical properties of PrP, leading to the activation of ER-dependent signaling pathways that controls cellular survival. Prion diseases or transmissible spongiform encephalopathies (TSEs) are neurodegenerative disorders affecting humans and animals, which are characterized by the presence of PrP Sc , an abnormal, protease-resistant isoform of the cellular prion protein, called PrP C [1]. The most common TSE in humans is Creutzfeldt-Jakob disease (CJD) affecting in average 1 new patient per million people each year. In animals the most common TSE is scrapie, which is an endemic disease affecting sheep and goats for centuries. However, it is the recent appearance of new TSEs that have put prions in the spotlight. These new diseases include variant CJD (vCJD) in humans, bovine spongiform encephalopathy (BSE) in cattle and chronic wasting disease (CWD) in elk and deer. Etiologically, prion diseases can be classified as infectious (iatrogenics or derived from the consumption of material contaminated with infectious prions), sporadic (spontaneous origin) or hereditary (inherited in an autosomic dominant manner). Around 90% of the CJD cases are sporadic. Inherited prion diseases in humans have been associated with different point mutations [2,3] and increased number of octapeptide repeats within the PrP open reading frame [4-9]. vCJD is the newest and most frightening member of the TSE group. It appearance in 1996 has been undoubtedly linked to the BSE outbreak and despite that the number of new cases of vCJD seems to be decreasing, there is an enormous concern of secondary transmission of *Address correspondence to this author at the University of Texas Medical Branch, Galveston, TX77555, USA; E-mail: clsoto@utmb.edu vCJD among humans [10-13]. Indeed, a recent report has raised the possibility of propagation of the disease through blood transfusion [14]. The infectious agent associated to TSE, called a prion, belongs to a new class of unprecedent agents whose nature and pathogenesis is not yet fully understood. While the chemical nature of the prion remains unclear, compelling evidence suggest that misfolded PrP Sc might be its major or even its only component [15]. It is proposed that prion replicates by interaction of the incoming PrP Sc with the host PrP C leading to the transformation of the normal protein into the pathological one. The mechanism of the interaction between PrP C and PrP Sc is unclear, but two steps have been identified in cell free studies: binding of PrP C to PrP Sc followed by misfolding, oligomerization and acquisition of protease resistance [16]. Although TSEs are diseases without a unique etiology or clinical profile, the characteristic of brain damage are similar. Extensive spongiform degeneration, large extent of neuronal loss, synaptic alterations, atypical brain inflammation and accumulation of protein aggregates are typical features of TSE [17]. However, the relationship of the prion protein and its structural conversion with brain damage is for the most part obscure. Neuronal loss is a salient feature of prion diseases [18]. Several studies in humans and in mice models of diverse types of prion diseases (infectious models, hereditary models with mutated PrPs and transgenic models overexpressing wild type PrP) indicate that neuronal dysfunction and death occur through a specific mechanism denominated apoptosis [19-25]. Transgenic mice expressing a PrP insertional