title: Loss of prion protein leads to age-dependent behavioral abnormalities and changes in cytoskeletal protein expression.
abstract: The cellular prion protein (PrPC) is a highly conserved protein whose exact physiological role remains elusive. In the present study, we investigated age-dependent behavioral abnormalities in PrPC-knockout (Prnp0/0) mice and wild-type (WT) controls. Prnp0/0 mice showed age-dependent behavioral deficits in memory performance, associative learning, basal anxiety, and nest building behavior. Using a hypothesis-free quantitative proteomic investigation, we found that loss of PrPC affected the levels of neurofilament proteins in an age-dependent manner. In order to understand the biochemical basis of these observations, we analyzed the phosphorylation status of neurofilament heavy chain (NF-H). We found a reduction in NF-H phosphorylation in both Prnp0/0 mice and in PrPC-deficient cells. The expression of Fyn and phospho-Fyn, a potential regulator for NF phosphorylation, was associated with PrPC ablation. The number of β-tubulin III-positive neurons in the hippocampus was diminished in Prnp0/0 mice relative to WT mice. These data indicate that PrPC plays an important role in cytoskeletal organization, brain function, and age-related neuroprotection. Our work represents the first direct biochemical link between these proteins and the observed behavioral phenotypes.
authors.affiliation: Department of Neurology, University Medical Center Göttingen, Robert-Koch-Straße 40, 37075, Göttingen, Germany, Matthias.Schmitz@med.uni-goettingen.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmitz
authors.forename: Catharina
authors.initials: C
authors.lastname: Greis
authors.forename: Philipp
authors.initials: P
authors.lastname: Ottis
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Silva
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Schulz-Schaeffer
authors.forename: Arne
authors.initials: A
authors.lastname: Wrede
authors.forename: Katharina
authors.initials: K
authors.lastname: Koppe
authors.forename: Bruce
authors.initials: B
authors.lastname: Onisko
authors.forename: Jesús R
authors.initials: JR
authors.lastname: Requena
authors.forename: Nambirajan
authors.initials: N
authors.lastname: Govindarajan
authors.forename: Carsten
authors.initials: C
authors.lastname: Korth
authors.forename: Andre
authors.initials: A
authors.lastname: Fischer
authors.forename: Inga
authors.initials: I
authors.lastname: Zerr
mesh_terms: D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D003214:Conditioning, Classical / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D003599:Cytoskeleton / Q000235:genetics* / Q000378:metabolism; D005239:Fear; D007858:Learning / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D018621:PrPC Proteins / Q000235:genetics* / Q000378:metabolism; D040901:Proteomics; D021641:Recognition, Psychology / Q000502:physiology
chemical_list: D003598:Cytoskeletal Proteins; D018621:PrPC Proteins