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J. Biol. Chem., Vol. 280, Issue 2, 1264-1271, January 14, 2005

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Altered Interaction and Expression of Proteins Involved in Neurosecretion in Scrapie-infected GT1-1 Cells^*

Malin K. Sandberg and Peter Löw

From the Department of Neuroscience, Karolinska Institutet, Retzius väg 8 B2: 5, Stockholm, S-171 77, Sweden

Prions cause transmissible and fatal diseases that are associated with spongiform degeneration, astrogliosis, and loss of axon terminals in the brains. To determine the expression of proteins involved in neurosecretion and synaptic functions after prion infection, gonadotropin-releasing hormone neuronal cell line subclone (GT1-1) was infected with the RML scrapie strain and analyzed by Western blotting, real time PCR, and immunohistochemistry. As revealed by Western blotting of lysates exposed to different temperatures, the levels of complexed SNAP-25, syntaxin 1A, and synaptophysin were decreased in scrapie-infected GT1-1 cells (ScGT1-1), whereas the level of monomeric forms of these proteins was increased and correlated to the level of scrapie prion protein (PrP^Sc). However, when complex formation was prevented by prolonged heating of samples in SDS, the levels of monomeric SNAP-25, syntaxin 1A and synaptophysin in ScGT1-1 cells were decreased in comparison to GT1-1 cells. The reduced level of SNAP-25 was observed as early as 32 days postinfection. Increased mRNA levels of both splice variants SNAP-25a and -b in ScGT1-1 cells were seen. No difference in the morphology, neuritic outgrowth or distribution of SNAP-25, syntaxin 1A, or synaptophysin could be observed in ScGT1-1 cells. Treatment with quinacrine or pentosan polysulfate cleared the PrP^Sc from the ScGT1-1 cell cultures, and the increase in levels of monomeric SNAP-25 and synaptophysin was reversible. These results indicate that a scrapie infection can cause changes in the expression of proteins involved in neuronal secretion, which may be of pathogenetic relevance for the axon terminal changes seen in prion-infected brains.

Received for publication, October 7, 2004

^* This study was supported by grants from the Swedish Foundation for Strategic Research (EU QLK2-CT-2002.8162 and FOOD-CT-2004-5065) and the United States Army (DAMD17-03-102288). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Neuroscience, Karolinska Institutet, Retzius väg 8 B2:5, S-171 77 Stockholm, Sweden. Tel.: 46-8-524-878-10; Fax: 46-8-325-325; E-mail: malin.sandberg{at}neuro.ki.se.

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