Mutant prion protein D202N associated with familial prion disease is retained in the endoplasmic reticulum and forms ‘curly’ intracellular aggregates

Abstract

Transmissible Spongiform Encephalopathies are fatal neurodegenerative disorders of humans and animals that are familial, sporadic, and infectious in nature. Familial disorders of humans include Gerstmann-Straussler-Scheinker disease (GSS), familial Creutzfeldt-Jakob disease (CJD), and fatal familial insomnia, and result from point mutations in the prion protein gene. Although neurotoxicity in familial cases is believed to result from a spontaneous change in conformation of mutant prion protein (PrP) to the pathogenic PrP-scrapie (PrPSc) form, emerging evidence indicates otherwise. We have investigated the processing and metabolism of mutant PrP D202N (PrP202N) in cell models to elucidate possible mechanisms of cytotoxicity. In this report, we demonstrate that PrP202N expressed in human neuroblastoma cells fails to achieve a mature conformation following synthesis and accumulates in the endoplasmic reticulum as 'curly' aggregates. In addition, PrP202N cells show increased sensitivity to free radicals, indicating that neuronal susceptibility to oxidative damage may account for the neurotoxicity observed in cases of GSS resulting from PrP D202N mutation.

Conformational conversion of prion protein in prion diseases

“…The mutations within the hydrophobic domain G114V, A117V, and G131V showed an effect on translocation, resulting in slightly increased generation of a topological particular trans-membrane form [38]. Human PrP mutant D202N that is expressed in human neuroblastoma cells fails to fold into a mature conformation and accumulates in the endoplasmic reticulum as curly aggregates [39].…”

Characterization of mutations in <em>PRNP</em> (prion) gene and their possible roles in neurodegenerative diseases

“…This patient had PSP-like symptoms, such as akinetic rigidity, gait and postural disturbances, hyperreflexia, and dementia. 124 , 125 In 2013, the mutation was reported in probably a de novo GSS case (Caucasian female from Germany) with parkinsonism and gaze impairment. The patient was homozygous for the V/V allele for codon 129.…”

“…α3-Helix is an anatomic helix, resulted by the conserved capping box and by the ionic bond, located between E200 and K204, and the mutation might result in decreased stability in this complex. 125 …”

Iron in Neurodegenerative Disorders of Protein Misfolding: A Case of Prion Disorders and Parkinson's Disease

“…Most are in the relatively structured C-terminal region, although an insertion in the N-terminal octapeptide repeat region is also associated with a familial prion disorder. Most mutations alter the trafficking and/or turnover of the mutant protein in a manner that is specific to each mutation, and the associated cytotoxicity is influenced by the post-translational modifications, aggregation state, and the subcellular localization where the mutant protein accumulates (11,(54)(55)(56)(57)(58)(59)(60)181). Some of the mutations alter cellular iron metabolism, and specific instances are discussed below.…”