Mutant Prion Protein D202N Associated with Familial Prion Disease is Retained in the Endoplasmic Reticulum and Forms `Curly' Intracellular Aggregates

Authors: Gu, Yaping¹; Verghese, Susamma¹; Bose, Sharmila¹; Mohan, Maradumane²; Singh, Neena³

Source: Journal of Molecular Neuroscience, Volume 32, Number 1, May 2007 , pp. 90-96(7)

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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 (PrP^Sc) form, emerging evidence indicates otherwise. We have investigated the processing and metabolism of mutant PrP D202N (PrP^202N) in cell models to elucidate possible mechanisms of cytotoxicity. In this report, we demonstrate that PrP^202N expressed in human neuroblastoma cells fails to achieve a mature conformation following synthesis and accumulates in the endoplasmic reticulum as `curly' aggregates. In addition, PrP^202N 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.

Keywords: GSS D202N; Oxidative stress; Curly aggregates; Inherited disease; Prion disorders

Document Type: Research article

DOI: http://dx.doi.org/10.1007/s12031-007-0023-6

Affiliations: 1: Institute of Pathology, Case Western Reserve University, 2085, Adelbert Road, Cleveland, OH, 44106, USA, 2: Institute of Pathology, Case Western Reserve University, 2085, Adelbert Road, Cleveland, OH, 44106, USA, Email: maradumane.mohan@case.edu 3: Institute of Pathology, Case Western Reserve University, 2085, Adelbert Road, Cleveland, OH, 44106, USA, Email: neena.singh@case.edu

Publication date: 2007-05-01

Mutant Prion Protein D202N Associated with Familial Prion Disease is Retained in the Endoplasmic Reticulum and Forms `Curly' Intracellular Aggregates

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