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Web Date: June 21, 2012

Prions Partner Up With DNA

Biochemistry: The disease-causing proteins bind to DNA and form toxic aggregates
Department: Science & Technology | Collection: Life Sciences
News Channels: Biological SCENE
Keywords: prion, DNA-protein interactions, aggregation, transmissible spongiform encephalopathy, TSE
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TOXIC BONDING
By themselves, prion proteins don’t clump much (top, scale bar represents 20 µm). But when the 18-base-pair D44 DNA sequence binds with prions (center, scale bar 20 µm), aggregates of the proteins form. The 21-base-pair D67 sequence complexes with prions (bottom, scale bar 50 µm) to form even larger aggregates. Images are from transmission electron microscopy.
Credit: Yraima Cordeiro
20120621lnj1-proteinarray
 
TOXIC BONDING
By themselves, prion proteins don’t clump much (top, scale bar represents 20 µm). But when the 18-base-pair D44 DNA sequence binds with prions (center, scale bar 20 µm), aggregates of the proteins form. The 21-base-pair D67 sequence complexes with prions (bottom, scale bar 50 µm) to form even larger aggregates. Images are from transmission electron microscopy.
Credit: Yraima Cordeiro

Prion proteins, famous for causing mad cow and Creutzfeldt-Jakob diseases, have long posed a mystery to scientists. They seem to replicate and spread disease without the participation of genetic material. But researchers have for the first time identified DNA interactions that lead to prion aggregation and cell toxicity (Biochemistry, DOI: 10:1021/bi300440e).

Scientists think that prions serve as cell-signaling proteins in the nervous system. But misfolded prions can become infectious, causing transmissible spongiform encephalopathies such as mad cow disease. The protein-only hypothesis for TSE diseases holds that when infectious prions encounter typical prions on extracellular membranes, they convert them to infectious forms that continue spreading. The misfolded prions then start clumping together into aggregates, killing nerve cells, scientists have found.

Yraima Cordeiro and Jerson L. Silva of the Federal University of Rio de Janeiro and their colleagues wondered whether DNA might take part in prion diseases. Previous studies by them and other researchers had shown that nucleotides can bind to prions, so the group decided to mix normal mouse prions with two short, doubled-stranded DNA sequences that they call D44 and D67. The resultant prion-DNA complexes aggregated into clumps, which the researchers observed using three spectroscopic techniques and transmission electron microscopy. The prions alone didn’t aggregate. Both types of prion-DNA aggregates also killed neuroblastoma cells, the researchers found.

Using D67, D44, and two additional variants of each sequence, the researchers tried to figure out which characteristics might be responsible for the aggregation and toxicity of the prion-DNA complexes. The properties they examined were sequence length, specific base-pair order, and the number of guanine and cytosine bases. The only variable that seemed to matter was DNA sequence length: The 21-base-pair sequences led to larger prion aggregates than did the 18-base-pair sequences.

Cordeiro and her team’s work shows how biomacromolecules other than proteins, such as nucleic acids, might take part in prion-mediated diseases such as TSEs, says Rafael Giraldo, who studies the aggregation of proteins and DNA at Spain’s National Research Council. The interactions Cordeiro saw between DNA and prions don’t adhere to the protein-only aspect of the traditional hypothesis of prion disease transmission, he adds. But the research doesn’t contradict the central idea that proteins are the infectious agent. That’s because, Giraldo says, the nucleic acids in the study do not encode genetic information required for prion propagation.

The assistance of another molecule in prion disease development could help explain the prion species barrier, Cordeiro says. The prions in different organisms are very similar in amino acid sequence, but one organism’s infectious prions rarely cause disease in other species. Each species might require a different helper biomolecule to get prions to aggregate, she says. Her team is now studying a wider range of nucleic acid sequences to determine whether they play a role in prion toxicity and infectivity.

 
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