Abstract
Prion protein (PrP) mutations are linked to genetic prion diseases, a class of phenotypically heterogeneous neurodegenerative disorders with invariably fatal outcome. How mutant PrP triggers neurodegeneration is not known. Synaptic dysfunction precedes neuronal loss but it is not clear whether, and through which mechanisms, disruption of synaptic activity ultimately leads to neuronal death. Here we show that mutant PrP impairs the secretory trafficking of AMPA receptors (AMPARs). Specifically, intracellular retention of the GluA2 subunit results in synaptic exposure of GluA2-lacking, calcium-permeable AMPARs, leading to increased calcium permeability and enhanced sensitivity to excitotoxic cell death. Mutant PrPs linked to different genetic prion diseases affect AMPAR trafficking and function in different ways. Our findings identify AMPARs as pathogenic targets in genetic prion diseases, and support the involvement of excitotoxicity in neurodegeneration. They also suggest a mechanistic explanation for how different mutant PrPs may cause distinct disease phenotypes.
Highlights
Synaptic dysfunction is an early process in prion disease, preceding synapse loss and neuronal death
Genetic prion diseases are degenerative brain disorders caused by mutations in the gene encoding the prion protein (PrP)
We show that mutant PrP alters the subunit composition of glutamate amino3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, promoting cell surface exposure of GluA2-lacking, calcium-permeable receptors, increasing neuronal vulnerability to excitotoxic cell death
Summary
Synaptic dysfunction is an early process in prion disease, preceding synapse loss and neuronal death. We describe morphological and functional alterations in neurons expressing prion protein (PrP) mutations associated with genetic prion disease, indicating a neurotoxic mechanism involving α-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs). Genetic prion diseases are rare and currently untreatable neurodegenerative disorders linked to mutations in the PRNP gene, encoding PrP, on chromosome 20 [1]. A noteworthy example is prion disease linked to the substitution of asparagine (N) for aspartic acid (D) at codon 178 which, depending on the amino acid at codon 129 on the mutant allele, segregates with either FFI (D178N/M129), primarily characterized by severe sleep disorders and autonomic dysfunction, or CJD178 (D178N/V129), clinically identified by global cortical dementia and motor abnormalities [2]
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