Blood test closer for mad cow disease, Alzheimers and Parkinson's
by: Pia Akerman From:The Australian
September 12, 201210:51AM
BLOOD tests to diagnose Alzheimers disease, Parkinson's and the human form
of mad cow disease could be closer thanks to new Australian research.
Research by University of Melbourne scientists, published in the Nucleic
Acids Research journal this week, has identified specific particles (exosomes)
released by cells infected with prions, the pathogen that causes diseases such
as human variant Creutzfeldt-Jakob disease.
It raises the possibility of a diagnostic blood test identifying the
exosomes in the blood stream.
Thousands of Australians are currently banned from donating blood because
they lived in the UK when mad cow disease was present in local beef and there is
no easy test to identify the risk.
Since 2004 a small number of British residents have been diagnosed with
vCJD transmitted through blood transfusion.
University of Melbourne associate professor Andrew Hill, who worked on the
research, said further testing was needed.
He said while Alzheimer's and Parkinson's were not transmissible like prion
diseases such as vCJD, they similarly released the exosome particles.
"Our thinking is that they might too have a unique signature on them that
we could potentially pick up in blood as well," he said.
"Obviously these brain diseases are hard to diagnose because you need very
extensive imaging tests to see what's going on inside the brain."
The Red Cross has previously said its ban on blood donations from people
who lived in the UK between 1980 and 1996 for more than six months, or received
blood transfusions there, would remain until there was a reliable blood
screening test for vCJD.
Nucleic Acids Research Advance Access published September 10, 2012
Nucleic Acids Research, 2012, 1–13 doi:10.1093/nar/gks832
Small RNA deep sequencing reveals a distinct miRNA signature released in
exosomes from prion-infected neuronal cells
Shayne A. Bellingham1,2, Bradley M. Coleman1,2 and Andrew F. Hill1,2,3,*
1Department of Biochemistry and Molecular Biology,
2Bio21 Molecular Science and Biotechnology Institute and
3Mental Health Research Institute, The University of Melbourne, Parkville,
Victoria 3010, Australia
Received December 8, 2011; Revised and Accepted August 9, 2012
ABSTRACT
Prion diseases are transmissible neurodegenerative disorders affecting both
humans and animals. The cellular prion protein, PrPC, and the abnormal
infectious form, PrPSc, are found associated with exosomes, which are small
50–130nm vesicles released from cells. Exosomes also contain microRNAs (miRNAs),
a class of non-coding RNA, and have been utilized to identify miRNA signatures
for diagnosis of disease. While some miRNAs are deregulated in prion-infected
brain tissue, the role of miRNA in circulating exosomes released during prion
disease is unknown. Here, we investigated the miRNA profile in exosomes released
from prion-infected neuronal cells. We performed the first small RNA deep
sequencing study of exosomes and demonstrated that neuronal exosomes contain a
diverse range of RNA species including retroviral RNA repeat regions, messenger
RNA fragments, transfer RNA fragments, noncoding RNA, small nuclear RNA, small
nucleolar RNA, small cytoplasmic RNA, silencing RNA as well as known and novel
candidate miRNA. Significantly, we show that exosomes released by prion-infected
neuronal cells have increased let-7b, let-7i, miR-128a, miR-21, miR-222,
miR-29b, miR-342-3p and miR-424 levels with decreased miR-146 a levels compared
to non-infected exosomes. Overall, these results demonstrate that circulating
exosomes released during prion infection have a distinct miRNA signature that
can be utilized for diagnosis and understanding pathogenic mechanisms in prion
disease.
snip...
While this hypothesis remains to be tested, these observations leave open
the possibility that miRNAs are packaged into exosomes as a result of PrPC
binding AGO1 and AGO2 promoting formation of miRISCs on the MVB, which functions
as checkpoint for scanning mRNAs. Therefore selecting AGO-bound complementary
mRNA:miRNAs that are to be repressed, while non-complementary miRNAs are
packaged into ILVs along with PrPC and released with exosomes. Whether
misfolding of PrPC into PrPSc during prion disease infection alters its ability
to bind to Argonaute proteins, modulates the function of miRISC on the MVB and
subsequent release of miRNA in exosomes during prion diseases certainly deserves
investigation. Given that, we have identified significant changes in particular
miRNA species released in association with exosomes from prion-infected cells,
its plausible to suggest that miRNAs are selectively packaged as a direct result
of PrPC and PrPSc and its influence on the miRNA biogenesis pathway. In summary,
our results strongly support the hypothesis that exosomes released from
prion-infected neuronal cells have a distinct miRNA signature that may be
utilized for the identification of prion infection. This signature comprises
significant increases in let-7 b, let-7i, miR-128 a, miR-21, miR-222, miR-29 b,
miR-342-3 p and miR-424 with decreased miR-146 a detection and agrees to some
extent to previously reported miRNA changes detected in brains of terminally
infected mouse and primate models of prion disease, and sporadic CJD samples
(17,18). Evaluation of our exosomal miRNA signature in circulating exosomes
derived from clinical plasma samples from sporadic and variant forms of human
prion disease and in animal models infected with different prion strains will be
the subject of our further studies. Importantly, it has been shown the miRNAs
deregulated in prion-infected exosomes identified in this study have also been
detected in circulating exosomes isolated from human serum samples (14), and
that neither have currently been detected in disease-associated exosomes in the
current literature and a search of ExoCarta database (58), suggesting that this
miRNA signature has significant and specific diagnostic potential. However, it
should be noted that our study also identified other ncRNAs and mRNA fragments
(Supplementary Figure S1) that may also be deregulated in exosomes released from
prioninfected neuronal cells. Furthermore, it has been identified that
extracellular miRNA released from cells into plasma can associate in two
populations, both dependent and independent of exosomes either bound to AGO2
(59–61) or high-density lipoproteins (62). Therefore, targeted exosomal
purification strategies for enrichment of circulating miRNA biomarkers may be
required to increase biomarker sensitivity (14,15,23). This research also has
potential diagnostic implications for other neurodegenerative diseases in which
exosomes have been identified to play a role including Alzheimer’s disease (63–
65), amyotrophic lateral sclerosis (66) and Parkinson’s disease (67).
snip...
Endogenous Viral Etiology of Prion Diseases
Thursday, August 16, 2012
Blood products, collected from a donor who was at risk for variant
Creutzfeldt-Jakob disease ( vCJD) USA JUNE, JULY, AUGUST 2012
Wednesday, May 16, 2012
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Proposal ID: 29403
http://betaamyloidcjd.blogspot.com/2012/05/alzheimers-disease-and-transmissible.html
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