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Title: Loss of prion protein leads to age-dependent behavioral abnormalities and changes in cytoskeletal protein expression

Author
item SCHMITZ, MATTHIAS - National Reference Laboratory For Bse
item GREIS, CATHARINA - National Reference Laboratory For Bse
item OTTIS, PHILIPP - Heinrich-Heine University
item Silva, Christopher - Chris
item SCHULZ-SCHAEFFER, WALTER - Georg August University
item WREDE, ARNE - Georg August University
item KOPPE, KATHARINA - Heinrich-Heine University
item ONISKO, BRUCE - Oni Pro Biosciences
item REQUENA, JESUS - University Of Santiago De Compostela
item GOVINDARAJAN, NAMBIRAJAN - Deutsches Zentrum Für Neurodegenerative Erkrankungen (DZNE)
item KORTH, CARSTEN - Heinrich-Heine University
item FISHER, ANDRE - Deutsches Zentrum Für Neurodegenerative Erkrankungen (DZNE)
item ZERR, INGA - National Reference Laboratory For Bse

Submitted to: Molecular Neurobiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/29/2014
Publication Date: 3/7/2014
Citation: Schmitz, M., Greis, C., Ottis, P., Silva, C.J., Schulz-Schaeffer, W., Wrede, A., Koppe, K., Onisko, B., Requena, J.R., Govindarajan, N., Korth, C., Fisher, A., Zerr, I. 2014. Loss of prion protein leads to age-dependent behavioral abnormalities and changes in cytoskeletal protein expression. Molecular Neurobiology. DOI: 10.1007/s12035-014-8655-3; 50(3):923-936.

Interpretive Summary: The normal cellular prion protein(PrPC)is an important brain protein whose exact function is poorly understood. We used matched sets of ordinary mice that are able to make PrPC and transgenic mice that are not able to make PrPC. Both sets of mice were subjected to a battery of standard behavioral tests at 3, 9, and 20 months. The transgenic mice and ordinary mice behaved differently. The ordinary mice built better nests, had better memories, and learned faster than the transgenic mice. Next, we wanted to compare cells from normal mice and transgenic mice to see if they had different protein profiles. We found more of four proteins in older normal mice but not in older transgenic mice. Another five proteins were found in different amounts in cells from normal mice than in transgenic mice. All of these proteins were involved in organizing the scaffolding that gives these cells their structure. We now understand that PrPC is involved in maintaining the scaffolding in cells. PrPC also has a role in minimizing age-dependent changes in the brain.

Technical Abstract: Cellular prion protein (PrPC) is a multifunctional protein, whose exact physiological role remains elusive. Since previous studies indicated a neuroprotective function of PrPC, we investigated whether Prnp knockout mice(Prnp0/0)display age-dependent behavioral abnormalities. Matched sets of Prnp0/0 and wild type (WT) mice were subjected to a battery of standardized behavioral tasks at various times in their lives. We found that PrPC-dependent behavioral deficits in memory performance and associative learning and basal anxiety behavior significantly increased with age. Moreover, we observed for the first time deficits in nest building behavior of Prnp0/0 mice at all ages Previous work on PrPC over-expressing cells provided evidence for an involvement of PrPC in the physiology of the cytoskeleton. In vitro experiments revealed a correlation between PrPC expression and phosphorylation of the heavy neurofilament subunit(NF-H).Therefore, we performed a hypothesis-driven proteomic analysis of cytoskeletal proteins using the ICAT(isotope coded affinity tag) labeling strategy and tubulin-staining. Our experiments revealed that four NF proteins (NF-H, NF-M, NF-L, and alpha-internexin) were upregulated in aged WT but not in aged Prnp0/0 mice and the phosphorylation status of NF was decreased in Prnp0/0 mice. Another five proteins (NF-H, NF-L, spectrin, alpha-internexin and vimentin)were differentially regulated in WT and Prnp0/0 mice. Also, a substantially higher number of '-tubulin III-positive neurons in the hippocampus of WT animals could be detected. These data provide evidence for an important role of PrPC in cytoskeleton-organization and brain function and give hints for a potential neuroprotective role of PrPC against age-dependent changes in the brain.