Synaptic Dysfunction in Prion Diseases: A Trafficking Problem?

Abstract

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 (PrPC). Experimental data suggest that accumulation of misfolded PrPC 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 PrPC impairs the secretory trafficking of calcium channels essential for synaptic function, we propose a model of pathogenicity in which intracellular retention of misfolded PrPC results in loss of function or gain of toxicity of PrPC-interacting proteins. This neurotoxic modality may also explain the phenotypic heterogeneity of prion diseases.

Transgenic Fatal Familial Insomnia Mice Indicate Prion Infectivity-Independent Mechanisms of Pathogenesis and Phenotypic Expression of Disease

“…Since artificial targeting of PrP to the Golgi results in intracellular retention of α 2 δ-1 [ 15 ], D177N/M128 may also impair VGCC transport and function in CGNs, contributing to the motor dysfunction of Tg(FFI), as in Tg(PG14) and Tg(CJD) mice. However, there could be other PrP C -interacting proteins whose cellular trafficking and synaptic targeting may be affected differently by the different mutants, potentially triggering specific neurotoxic effects [ 70 ]. PrP C interacts physically with the NR1 and NR2D subunits of N-methyl-D-aspartate (NMDA) and the GluA1 and GluA2 subunits of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and these interactions are important for normal neuronal physiology and survival [ 71 – 73 ].…”

“…Moreover, different mutants interact differently with receptor subunit isoforms expressed in functionally distinct neurons of the brain [ 73 ]. Thus, different mutant PrPs may have different effects on the function and survival of different neurons—hence on the clinical presentation of disease—depending on where in the secretory pathway they preferentially localize, and how this interferes with the transport of the molecules they interact with [ 70 ].…”

Prion Protein Modulates Monoaminergic Systems and Depressive-like Behavior in Mice

“…Synaptic dysfunction and damage are prominent features of prion pathology, as seen both in post-mortem tissue of human patients and in animal models of the disease (96,97). Several reports emerged in the last decade associating PrP C to synaptic function, structure, and plasticity (98) as well as memory and behavioral processes (99), often through the cAMP/PKA pathway.…”

Review: PrP 106‐126 – 25 years after

“…Interfering with apoptosis proved to be effective against PrP106‐126 neurotoxicity . However, in prion diseased brains, apoptosis is the last step of a neurodegenerative process in which synapses are first involved and deletion of proapoptotic genes rescued neurones but had no effect on synaptic disruption and clinical signs in mouse models of genetic or acquired prion disease .…”