Saturday, July 23, 2011

They're Bad, But Can They Be Good?

Prions are known as infectious agents, but is it possible that they are an evolutionary adaptation in mammals that sometimes goes awry? First studied for their part in neurodegenerative diseases called transmissible spongiform encephalopathies (TSE) (mad cow disease in bovines, scrapie in ovines and Creutzfeldt-Jakob disease in humans) the role and function of normal prions has taken longer to determine.

Prions are proteins in misfolded form. They are different from other known infectious agents – viruses, bacteria, fungi, and parasites – all of which contain nucleic acids (either DNA, RNA, or both). A prion contains no nucleic acids. Misfolded prions are infectious by their effect on normal versions of the prion protein. A prion replicates by inducing other properly-folded proteins to convert into the disease-associated, prion form; the prion acts as a template to guide the misfolding of more protein into prion form. These newly misfolded prions then go on to convert more proteins themselves, triggering a chain reaction that produces large amounts of the misfolded prion form. All known prions induce the formation of an amyloid fold. Amyloid aggregates are fibrils, growing at their ends, and replicating when breakage causes two growing ends to become four growing ends. The incubation period of prion diseases is determined by the exponential growth rate associated with prion replication. The propagation of the prion depends on the presence of normally-folded protein in which the prion can induce misfolding; animals which do not express the normal form of the prion protein cannot develop or transmit the disease.

In a study done by Gerald Zamponi and colleagues it has been discovered that prions actually may have a good side. When not abnormally folded, the presence of prions has been shown to inhibit the activity of certain neurons; acting as a check or balance on the overexcitation of certain neural transmissions - protecting the longevity of the neuron by keeping it from running itself to an early death.

In this study the brain activity of knockout mice (PrP-null) which lacked the prion protein was examined and compared with the brain activity of wild-type mice in which the prion protein was present. It was found that the neurons of the knockout mice responded longer and more vigorously to electrical or drug-induced stimulation than did neurons of the wild-type mice that had normal prion protein. Both brains showed similar waveform patterns, with waveforms exhibiting a robust presynaptic volley, a sharp downward deflecting population spike, and upward deflecting field excitatory postsynaptic potential as well as robust paired-pulse facilitation. However the PrP-null mice showed an increase in the number of overriding polyspikes. This suggested to the researchers that neurons in PrP-null mice fired multiple action potentials in response to a single stimulus and indicated a basal increase in excitability. Further testing indicated that the enhanced excitability seen in the PrP-null mice was in large part caused by the activity of N-methyl-d-aspartate receptor (NMDAR). These receptors are known to play a part in neuronal excitability and excitotoxic neuronal cell death. Without the normal prion protein present to regulate or modulate these receptors, the neurons in the brains of these overreacted again and again eventually leading to early degeneration of the neuron.

The trick for scientists now is to determine just how to balance the good and the bad of prion proteins in the search for treatments and cures for the many forms of TSE’s. Prions may have a bad name right now, but unlocking the secrets to their proper workings may one day advance the cures for the diseases they cause.


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