Monday, December 13, 2010

Nuclease resistant circular DNAs copurify with infectivity in scrapie and CJD

FOUND IN: Health & Medicine

Virus-Like Structure Calls Into Question Origin of Diseases Such as “Mad Cow”

Published: December 10, 2010

New Haven, Conn. — A Yale University researcher has found virus-like genetic material within samples of Creutzfeldt-Jakob disease (CJD) and scrapie, a finding that challenges scientific consensus on the nature of these deadly brain-wasting diseases.

Many scientists say that transmissible spongiform encephalopathies (TSEs) — including CJD, scrapie and epidemic “mad cow” disease — are caused by a misfolded normal protein that spontaneously becomes infectious. This infectious prion form is transmitted without nucleic acid used by infectious agents such as viruses, they say.

But other scientists, such as Laura Manuelidis, professor of surgery at Yale School of Medicine, say a slow-acting virus may be the cause of TSEs.

In the study, published this week in the online edition of the Journal of Neurovirology, Manuelidis reports extracting new circular virus-like DNA sequences from infectious particles of three samples of CJD and scrapie. These viral signatures would not be expected to be found in CJD or scrapie samples if infected prions were the sole culprits in the disease, she said.

“These findings won’t end the TSE debate, but hopefully it will open the door to more discussions about the nature of the causal infectious agent in TSEs and other late onset neurological diseases” Manuelidis said.

While these sequences, called Sphinx elements, were only visible in preparations of the infectious particles, ultimately they were found at very low amounts in uninfected cells, the study reports. Manuelidis believes that more of these sequences may be discovered in preparations of other infectious particles.

“They are intriguing, not only for their function in TSEs, but also because they may have once been incorporated from distant bacterial viruses,” Manuelidis says.

PRESS CONTACT: Bill Hathaway 203-432-1322

http://opac.yale.edu/news/article.aspx?id=8094


Research Author: Yale University Last Updated: Dec 10, 2010 - 9:30:26 AM

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Virus-Like Structure Calls Into Question Origin of Diseases Such as “Mad Cow”

By Yale University Dec 10, 2010 - 9:27:45 AM

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(HealthNewsDigest.com) - New Haven, Conn. - A Yale University researcher has found virus-like genetic material within samples of Creutzfeldt-Jakob disease (CJD) and scrapie, a finding that challenges scientific consensus on the nature of these deadly brain-wasting diseases.

Many scientists say that transmissible spongiform encephalopathies (TSEs) — including CJD, scrapie and epidemic “mad cow” disease — are caused by a misfolded normal protein that spontaneously becomes infectious. This infectious prion form is transmitted without nucleic acid used by infectious agents such as viruses, they say.

But other scientists, such as Laura Manuelidis, professor of surgery at Yale School of Medicine, say a slow-acting virus may be the cause of TSEs.

In the study, published this week in the online edition of the Journal of Neurovirology, Manuelidis reports extracting new circular virus-like DNA sequences from infectious particles of three samples of CJD and scrapie. These viral signatures would not be expected to be found in CJD or scrapie samples if infected prions were the sole culprits in the disease, she said.

“These findings won’t end the TSE debate, but hopefully it will open the door to more discussions about the nature of the causal infectious agent in

TSEs and other late onset neurological diseases” Manuelidis said.

While these sequences, called Sphinx elements, were only visible in preparations of the infectious particles, ultimately they were found at very low amounts in uninfected cells, the study reports. Manuelidis believes that more of these sequences may be discovered in preparations of other infectious particles.

“They are intriguing, not only for their function in TSEs, but also because they may have once been incorporated from distant bacterial viruses,” Manuelidis says.

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Nuclease resistant circular DNAs copurify with infectivity in scrapie and CJD

Laura Manuelidis1

(1) Yale University Medical School, 333 Cedar Street, New Haven, CT 06510, USA

Laura Manuelidis Email: laura.manuelidis@yale.edu

Received: 14 September 2010 Revised: 19 October 2010 Accepted: 22 October 2010 Published online: 7 December 2010

Abstract

In transmissible encephalopathies (TSEs), it is commonly believed that the host prion protein transforms itself into an infectious form that encodes the many distinct TSE agent strains without any nucleic acid. Using a ?29 polymerase and chromatography strategy, highly infectious culture and brain preparations of three different geographic TSE agents all contained novel circular DNAs. Two circular “Sphinx” sequences, of 1.8 and 2.4 kb, copurified with infectious particles in sucrose gradients and, as many protected viruses, resisted nuclease digestion. Each contained a replicase ORF related to microviridae that infect commensal Acinetobacter. Infectious gradient fractions also contained nuclease-resistant 16 kb mitochondrial DNAs and analysis of >4,000 nt demonstrated a 100% identity with their species-specific sequences. This confirmed the fidelity of the newly identified sequences detailed here. Conserved replicase regions within the two Sphinx DNAs were ultimately detected by PCR in cytoplasmic preparations from normal cells and brain but were 2,500-fold less than in parallel-infected samples. No trace of the two Sphinx replicases was found in enzymes, detergents, or other preparative materials using exhaustive PCR cycles. The Sphinx sequences uncovered here could have a role in TSE infections despite their apparently symbiotic, low-level persistence in normal cells and tissues. These, as well as other cryptic circular DNAs, may cause or contribute to neurodegeneration and infection-associated tumor transformation. The current results also raise the intriguing possibility that mammals may incorporate more of the prokaryotic world in their cytoplasm than previously recognized.

Keywords Prion - Phi 29 polymerase - Acinetobacter plamids - Neurodegeneration - Cancer - Circovirus

http://www.springerlink.com/content/k201658k278254q6/fulltext.html


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Nuclease resistant circular DNAs copurify with infectivity in scrapie and CJD

Laura Manuelidis

Online First™, 7 December 2010

Nuclease resistant circular DNAs copurify with infectivity in scrapie and CJD

Laura Manuelidis Received: 14 September 2010 / Revised: 19 October 2010 / Accepted: 22 October 2010 # Journal of NeuroVirology, Inc. 2010

http://www.springerlink.com/content/k201658k278254q6/fulltext.pdf


http://www.springerlink.com/content/k201658k278254q6/fulltext.html


http://info.med.yale.edu/neurosci/faculty/manuelidis_main.html


http://www.yalesurgery.org/neuropathology/research/index.aspx


http://www.yalesurgery.org/neuropathology/research/prion.aspx


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