What the heck are prions for?
Prions are proteinaceous infectious agents that were first discovered because of their role in the etiology of transmissible spongiform encephalopathies (TSEs), a set of fatal neurological disorders that include Creutzfeldt-Jakob disease, scrapie and bovine spongiform encephalitis. TSEs arise from progressive misfolding of the endogenous cellular prion protein (Prp [PrPC]) into disease-associated scrapie form (PrPSc), which, in turn, disrupts normal cellular function and results in the formation of aggregates and amyloid-like plaques. Although there has been a clear association between PrPSc with these disease states, the cellular function of PrPC remains incompletely understood. PrPC is expressed across the entire central nervous system and at particularly high levels in the hippocampus, striatum, and frontal cortex, with apparently wide subcellular distribution, including synaptic sites. A synaptic role of PrPC is consistent with evidence from PrP-null mice showing deficits in spatial learning, altered long-term potentiation and increased excitability of hippocampal neurons. Several studies have also suggested that PrPC may provide neuroprotection. For example, cultured hippocampal neurons obtained from PrP-null mice show an increased apoptosis during oxidative stress. Mice lacking PrPC show increased neuronal damage after ischemic stroke, whereas protection is evident upon the viral-based overexpression of PrPC in rats. Finally, in several in vivo models of seizure activity, PrP-null mice showed increased mortality, likely as a consequence of hyperexcitability leading to excitotoxicity. The cellular and molecular basis for these effects remains unknown. Recent research shows that PrPC exerts a neuroprotective role by inhibiting excitotoxic cell death and that PrPC is a modulator of synaptic function and, consequently, neuronal excitability.
So that’s what prions are for!
Prion protein attenuates excitotoxicity by inhibiting NMDA receptors. J Cell Biol 2008 181: 551-565
It is well established that misfolded forms of cellular prion protein (PrP [PrPC]) are crucial in the genesis and progression of transmissible spongiform encephalitis, whereas the function of native PrPC remains incompletely understood. To determine the physiological role of PrPC, we examine the neurophysiological properties of hippocampal neurons isolated from PrP-null mice. We show that PrP-null mouse neurons exhibit enhanced and drastically prolonged N-methyl-D-aspartate (NMDA)–evoked currents as a result of a functional upregulation of NMDA receptors (NMDARs) containing NR2D subunits. These effects are phenocopied by RNA interference and are rescued upon the overexpression of exogenous PrPC. The enhanced NMDAR activity results in an increase in neuronal excitability as well as enhanced glutamate excitotoxicity both in vitro and in vivo. Thus, native PrPC mediates an important neuroprotective role by virtue of its ability to inhibit NR2D subunits.
Tags: Biology, Health, Medicine, Microbiology, Prions, Science
Great post AJC !!
I was aware of this latest work into the possible function/role of PrPc. Researchers are definately making headway as is described here. I would also mention the work of Prof Nigel Hooper, Bath Uni. who continues to produce really interesting research in this field. That’s not just my opinion.
FWIW, here’s a relevant section from my report of the 2005 CJD Foundation’s Annual Family Conference in 2005:-
“The function of normal PrP is unknown at the moment mentioned Dr David Kocisko.
(PrPc has been implicated in the transport and compartmentalisation of copper in the synapse. It probably has multiple other functions that parallel other pathways; experimental animals without PrPc survive and do not exhibit the symptoms of any one disease.
The normal cellular form of this protein, PrPc is highly conserved in mammals, and is widely expressed in embryogenesis. Techniques exist to delete or make ineffectual genes in mice. When a mice knockout of the PrPc (i.e. the gene for the protein was deleted in all cells) was made, the mice appeared normal. More recent data suggests however, that these mice had altered circadian rhythms and sleep patterns, which suggest a possible link to Fatal Familial Insomnia. The PrPc is a normal membrane protein in neurons. It is anchored to the membrane through a glycosyl-phosphatidyl inositol link, with the protein chain on the outside of the neuronal plasma membrane. The PrPc (without the PI link) is water soluble, protease sensitive, and consists of 42% alpha helix and 3% beta sheet. – Ed).”