Prion protein expression level alters regional copper, iron and zinc content in the mouse brain

Abstract

The central role of the prion protein (PrP) in a family of fatal neurodegenerate diseases has garnered considerable research interest over the past two decades. Moreover, the role of PrP in neuronal development, as well as its apparent role in metal homeostasis, is increasingly of interest. The host-encoded form of the prion protein (PrP(C)) binds multiple copper atoms via its N-terminal domain and can influence brain copper and iron levels. The importance of PrP(C) to the regulation of brain metal homeostasis and metal distribution, however, is not fully understood. We therefore employed synchrotron-based X-ray fluorescence imaging to map the level and distributions of several key metals in the brains of mice that express different levels of PrP(C). Brain sections from wild-type, prion gene knockout (Prnp(-/-)) and PrP(C) over-expressing mice revealed striking variation in the levels of iron, copper, and even zinc in specific brain regions as a function of PrP(C) expression. Our results indicate that one important function of PrP(C) may be to regulate the amount and distribution of specific metals within the central nervous system. This raises the possibility that PrP(C) levels, or its activity, might regulate the progression of diseases in which altered metal homeostasis is thought to play a pathogenic role such as Alzheimer's, Parkinson's and Wilson's diseases and disorders such as hemochromatosis.

Characterization of prion protein function by focal neurite stimulation

“…Although the pathogenic properties of PrP C have been intensely studied, its physiological role remains unclear. So far PrP C has been associated with several cellular processes, including cell signaling (Linden et al, 2008), survival (Aguzzi et al, 2008) and adhesion (Malaga-Trillo et al, 2009) as well as neuritogenesis (Loubet et al, 2012;Steele et al, 2006), differentiation (Hajj et al, 2007;Kanaani et al, 2005) and brain metal homeostasis (Pushie et al, 2011). PrP C interacts with different surface or transmembrane molecules, including laminin, laminin receptor precursor and neural cell adhesion molecule (NCAM)-family members, contributing to many of the above mentioned processes (Linden et al, 2008).…”

Could Intracrine Biology Play a Role in the Pathogenesis of Transmissable Spongiform Encephalopathies Alzheimer’s Disease and Other Neurodegenerative Diseases?

“…39 If PrP c is involved not just in copper transport but in buffering copper in a sensitive cellular compartment such as nucleus, its partial replacement in that compartment by PrP sc could lead to locally elevated copper concentrations and enhanced PrP c synthesis given that copper upregulates PRNP gene transcription. 37,40 This increase in PrP c then would serve as a ready substrate for conversion into PrP sc , not only as a result of seeding but also to a lesser extent by spontaneous conversion. Indeed, copper facilitates such conversion.…”

Disruption of Metal Homeostasis and the Pathogenesis of Prion Diseases

“…Furthermore, prion plaques in the patient brain reportedly contain low Cu and high Mn [11]. The expression level of PrP is correlated with the distribution of metals [12]. Here, we review our studies and other new findings for a current understanding of the link between trace elements and the pathogenesis of prion diseases.…”