How prions make you sick

dendritic spineTransmissible spongiform encephalopathies (TSEs) are rare, but always fatal, neurodegenerative disorders of humans and other mammals. They are characterized by long incubation periods, spongiform changes in the brain associated with loss of neurons, and the absence of host responses. TSEs are caused by infectious proteins called prions. Insight into how prions cause TSEs comes from the observation that exposure of neurons to prions causes retraction of dendritic spines (link to paper).

Early alterations in the nervous system caused by prions include changes in the synapse such as retraction of dendritic spines, the projections where synaptic contacts occur (illustrated; image credit). Understanding these pathologies has been difficult due to a lack of an appropriate neuronal culture system.

To determine if prions are toxic for neurons, primary neuronal cultures were prepared from mice and grown on layers of astrocytes. Addition of an infected brain homogenate from mice that had been inoculated with the scrapie prion, PrPsc, led within 24 hours to retraction of dendritic spines and a reduction in their number and area. Similar effects on dendritic spines were also observed when purified PrPsc was used.

No effects of brain homogenates were observed using neurons prepared from mice lacking the prion gene prnp. This observation might have been predicted because prion diseases do not occur in mice lacking the prnp gene. However only an N-terminal domain of PrPc (amino acids 23-31) is required for the loss of dendritic spines. It seems likely that this part of PrPc on neurons binds the pathogenic PrPsc form, leading to neuronal loss.

Normal prions (PrPc) are completely digested with the enzyme proteinase K, while the pathogenic prion PrPsc is relatively resistant. Proteinase K treated PrPsc retained the ability to cause retraction of dendritic spines, showing that amino acids 23-90 of the protein are not needed for synaptotoxicity.

Dendritic spines are responsible for excitatory postsynaptic transmission and have roles in learning and memory. Their retraction by pathogenic prions are likely early changes leading to the pathogenic consequences of TSEs. How prions cause spine retractions can now be determined using cultured neurons. It will also be possible to determine if similar mechanisms are involved in dendritic spine loss associated with other neurodegenerative diseases, such as Alzheimer’s, Huntington’s, and Parkinson’s diseases.

 

TWiV 378: Herpes plays DUBstep

TWiVOn episode #378 of the science show This Week in Virology, Greg Smith joins the TWiVirate to reveal how his lab discovered a switch that controls herpesvirus neuroinvasion, and then we visit the week’s news about Zika virus.

You can find TWiV #378 at microbe.tv/twiv, or you may listen below.

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TWiV 215: Illuminating rabies and unwrapping a SARI

On episode #215 of the science show This Week in Virology, Vincent, Alan, and Kathy review the finding that rabies virus infection alters but does not kill neurons, and provide an update on the novel coronavirus in the Middle East.

You can find TWiV #215 at www.microbe.tv/twiv.

Poliovirus

Poliovirus by Jason Roberts

Poliovirus is the etiologic agent of the paralytic disease known as poliomyelitis. It’s also the virus I’ve worked on for most of my career. The World Health Organization is in the midst of a massive effort to eradicate the disease, an undertaking that has encountered a number of obstacles. In coming posts I’d like to discuss the polio eradication effort, but first we need some background on poliovirus.

Poliovirus is a member of a family of viruses called the Picornaviridae. Viruses are classified into families, and then genera, based on many criteria, including physical and biological properties. The Picornaviridae includes many other human pathogens, such as Coxsackieviruses, echoviruses, enteroviruses, hepatitis A virus, and rhinoviruses (which cause the common cold). The International Committee for the Taxonomy of Viruses is responsible for virus classification and maintains the Universal Virus Database, where you can find information about most known viruses.

Poliovirus is a rather small and simple virus. It is composed of a shell, or capsid, made of protein, as shown.

The poliovirus capsid is about 30 nanometers in diameter. Within the capsid is the information to make new virus particles – a single molecule of ribonucleic acid, or RNA. In the image, part of the capsid has been cut away to reveal the viral RNA. When the virus infects a cell, the RNA genome enters the cell and programs it to make new virus particles. These virus particles are released from the cell and go on to infect new cells.

In humans, poliovirus is ingested, and replicates in cells of the gastrointestinal tract. Newly synthesized virus particles are released into the intestine and shed in the feces. Transmission of poliovirus to another human occurs through contact with virus-containing feces or contaminated water. After multiplying in the gastrointestinal tract, poliovirus may enter the spinal cord and brain. Destruction of motor neurons by the virus leads to limb paralysis.

Poliomyelitis became a common disease at the turn of the 20th century. Two vaccines were developed in the 1950s that can effectively prevent the disease – inactivated poliovaccine (IPV, developed by Jonas Salk) and live, oral poliovaccine (OPV, developed by Albert Sabin). In 1988 the World Health Organization announced that it would eradicate poliomyelitis from the globe by the year 2000. We’ll discuss that goal, and obstacles that might prevent it from being attained, in subsequent posts.