Schmitz, MatthiasMatthiasSchmitzGreis, CatharinaCatharinaGreisOttis, PhilippPhilippOttisSilva, Christopher J.Christopher J.SilvaSchulz-Schaeffer, Walter J.Walter J.Schulz-SchaefferWrede, ArneArneWredeKoppe, KatharinaKatharinaKoppeOnisko, BruceBruceOniskoRequena, Jesus R.Jesus R.RequenaGovindarajan, NambirajanNambirajanGovindarajanKorth, CarstenCarstenKorthFischer, AndreAndreFischerZerr, IngaIngaZerr2017-09-072017-09-072014https://resolver.sub.uni-goettingen.de/purl?gro-2/3568The 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 wildtype (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 beta-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.enreview10.1007/s12035-014-8655-3246043550003448657000163142012