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Proteasome inhibitors promote the sequestration of PrP^Sc into aggresomes within the cytosol of prion-infected CAD neuronal cells

¹ INRA, U892 Virologie Immunologie Moléculaires, F-78350 Jouy-en-Josas, France;
² Centre National de la Recherche Scientifique, FRE2942, Oncologie Virale F-94801 Villejuif, France

³ E-mail: michel.dron{at}jouy.inra.fr

Dysfunction of the ERAD/proteasome system is believed to contribute to the initiation or aggravation of neurodegenerative disorders associated with protein misfolding, and there is some evidence to suggest that proteasome dysfunctions might be implicated in prion disease. We investigated the effect of proteasome inhibitors on the biogenesis of both PrPC and PrPSc in CAD neuronal cells, a newly introduced prion cell system. In non-infected cells, proteasome impairment altered the intracellular distribution of PrPC, leading to a strong accumulation in the Golgi apparatus. Moreover, a detergent-insoluble and weakly protease-resistant PrP species, termed PrP26K, accumulated in the cells, were they prion-infected or not. However, we found no evidence that in infected cells, this PrP26K species converts into highly proteinase K resistant PrPSc. In the infected cultures, proteasome inhibition caused an increased intracellular aggregation of PrPSc that deposited into large aggresomes. Our findings strengthen the view that, in neuronal cells expressing wild type PrPC from the natural promoter, proteasomal impairment may affect both the process of PrPC biosynthesis and the subcellular sites of PrPSc accumulation, yet these two effects could be essentially disconnected.

Received 5 January 2009; accepted 29 March 2009.