Synaptic dysfunction is an important cause of neurological symptoms in prion diseases, a class of clinically heterogeneous neurodegenerative disorders caused by misfolding of the cellular prion protein ( ). Experimental data suggest that accumulation of misfolded in the endoplasmic reticulum (ER) may be crucial in synaptic failure, possibly because of the activation of the translational repression pathway of the unfolded protein response. Here, we report that this pathway is not operative in mouse models of genetic prion disease, consistent with our previous observation that ER stress is not involved. Building on our recent finding that ER retention of mutant impairs the secretory trafficking of calcium channels essential for synaptic function, we propose a model of pathogenicity in which intracellular retention of misfolded results in loss of function or gain of toxicity of -interacting proteins. This neurotoxic modality may also explain the phenotypic heterogeneity of prion diseases. 1. Introduction Prion diseases, also known as transmissible spongiform encephalopathies, are progressive and invariably fatal degenerative disorders of the central nervous system (CNS) that affect humans and other animals [1]. Creutzfeldt-Jakob disease (CJD), Gerstmann-Str？ussler-Scheinker (GSS) syndrome, and fatal familial insomnia (FFI) are the most common forms in humans; scrapie of the goat and sheep, bovine spongiform encephalopathy (BSE), and chronic wasting disease of deer and elk are the best-known examples of prion zoonoses [2]. Widespread neuronal loss, astrocytosis, spongiform change (vacuolation of the neuropil in the gray matter), and in some cases amyloid plaques are key neuropathological findings in prion diseases, which in humans usually present with loss of motor coordination and other motor abnormalities, dementia, and neurophysiological deficits [3]. Similarly to other progressive neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease, frontotemporal dementia, and the tauopathies, prion diseases can arise sporadically or be genetically inherited; however, they can also be acquired by infection [4]. This is dramatically illustrated by kuru, a prion disease of the Foré-speaking people of Papua New Guinea, which used to be transmitted among women and children by ritual cannibalism [5]. Other forms transmitted by infection are variant CJD (vCJD) due to consumption of BSE-infected meat products and iatrogenic CJD in recipients of cadaveric sources of human growth hormone or dura mater grafts or blood transfusions from asymptomatic donors
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