Cytoplasmic prion protein induces forebrain neurotoxicity.
The prion protein (PrP) is essential for the pathogenesis of prion disease. PrP has been detected in the cytosol of neurons and transgenic mice expressing PrP in the cytosol (cyPrP) under a pan-neuronal promoter developed rapid cerebellar granule neuron degeneration. Yet, it remains unclear whether cyPrP is capable to cause toxicity in other neuronal populations. Here, we report that transgenic mice expressing cyPrP in the forebrain neurons developed behavioral abnormalities including clasping and hyperactivity. These mice had reduced thickness in cortex and developed astrogliosis in hippocampal and cortical regions. Moreover, cyPrP in these mice was recognized by the A11 anti-oligomer antibody and was associated with the hydrophobic lipid core of membranes, indicating that cyPrP oligomer caused membrane perturbation contributes to cyPrP neurotoxicity. Together, our results clearly revealed that cyPrP is able to cause toxicity in different neuronal populations, supporting a role of cyPrP in PrP-mediated neurodegenerative disorders.
Wang
Xinhe
X
Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH 43210, USA.
Bowers
Stephanie L
SL
Wang
Fei
F
Pu
Xin-An
XA
Nelson
Randy J
RJ
Ma
Jiyan
J
D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D006720:Homozygote; D008051:Lipid Bilayers / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000378:metabolism* / Q000473:pathology; D018621:PrPC Proteins / Q000378:metabolism / Q000472:pathogenicity*; D017096:Prion Diseases / Q000473:pathology*; D016548:Prosencephalon / Q000473:pathology*
D008051:Lipid Bilayers; D018621:PrPC Proteins