Friday, September 1, 2017

MSA prions exhibit remarkable stability and resistance to inactivation

MSA prions exhibit remarkable stability and resistance to inactivation


Authors and affiliations

Amanda L. WoermanSabeen A. KazmiSmita PatelYevgeniy FreymanAbby OehlerAtsushi AoyagiDaniel A. MordesGlenda M. HallidayLefkos T. MiddletonSteve M. GentlemanSteven H. OlsonStanley B. PrusinerEmail author

Original Paper

First Online: 28 August 2017 


In multiple system atrophy (MSA), progressive neurodegeneration results from the protein α-synuclein misfolding into a self-templating prion conformation that spreads throughout the brain. MSA prions are transmissible to transgenic (Tg) mice expressing mutated human α-synuclein (TgM83+/−), inducing neurological disease following intracranial inoculation with brain homogenate from deceased patient samples. Noting the similarities between α-synuclein prions and PrP scrapie (PrPSc) prions responsible for Creutzfeldt–Jakob disease (CJD), we investigated MSA transmission under conditions known to result in PrPSc transmission. When peripherally exposed to MSA via the peritoneal cavity, hind leg muscle, and tongue, TgM83+/− mice developed neurological signs accompanied by α-synuclein prions in the brain. Iatrogenic CJD, resulting from PrPSc prion adherence to surgical steel instruments, has been investigated by incubating steel sutures in contaminated brain homogenate before implantation into mouse brain. Mice studied using this model for MSA developed disease, whereas wire incubated in control homogenate had no effect on the animals. Notably, formalin fixation did not inactivate α-synuclein prions. Formalin-fixed MSA patient samples also transmitted disease to TgM83+/− mice, even after incubating in fixative for 244 months. Finally, at least 10% sarkosyl was found to be the concentration necessary to partially inactivate MSA prions. These results demonstrate the robustness of α-synuclein prions to denaturation. Moreover, they establish the parallel characteristics between PrPSc and α-synuclein prions, arguing that clinicians should exercise caution when working with materials that might contain α-synuclein prions to prevent disease.


α-synuclein Neurodegeneration Propagation Proteinopathies Transmission models 


Minimise transmission risk of CJD and vCJD in healthcare settings Updated 10 August 2017


Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States revisited 2017

Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery. 

Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC. Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. 

Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them. 

*** Evidence For CJD TSE Transmission Via Endoscopes 1-24-3 Singeltary et al

re-Singeltary to Bramble et al Evidence For CJD/TSE Transmission Via Endoscopes 

Brief Definitive Report

Infectivity in bone marrow from sporadic CJD patients


Accepted manuscript online: 9 August 2017 DOI: 10.1002/path.4954 


Prion infectivity was recently identified in the blood of both sporadic and variant Creutzfeldt-Jakob disease (CJD) patients. In variant CJD (vCJD) the widespread distribution of prions in peripheral tissues of both asymptomatic and symptomatic patients is likely to explain the occurrence of the observed prionaemia. However, in sporadic CJD (sCJD) prion infectivity is described to be located principally in the central nervous system. In this study, we investigated the presence of prion infectivity in bone marrow collected after death in patients affected with different sCJD agents. Bioassays in transgenic mice expressing the human prion protein revealed the presence of unexpectedly high levels of infectivity in the bone marrow from seven out of eight sCJD cases. These findings may explain the presence of blood-borne infectivity in sCJD patients. They also suggest that the distribution of prion infectivity in peripheral tissues in sCJD patients could be wider than currently believed, with potential implications for the iatrogenic transmission risk of this disease. 

Saturday, June 17, 2017

PRION 2017 P115 α- Synuclein prions from MSA patients exhibit similar transmission properties as PrPSc prions

Terry S. Singeltary Sr.


Saturday, June 17, 2017

PRION 2017 P115 α- Synuclein prions from MSA patients exhibit similar transmission properties as PrPSc prions

P115 α- Synuclein prions from MSA patients exhibit similar transmission properties as PrPSc prions 

Dr. Amanda Woerman1,2, Dr. Smita Patel1, Sabeen Kazrni1, Abby Oehler1, Yevgeniy Freyman1, Dr. Daniel Mordes3, Dr. Glenda Halliday4, Dr. Lefkos Middleton5, Dr. Steve Gentleman6, Dr. Steven Olson1,2, Dr. Stanley Prusiner1,2,7 

1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, United States, 
2Department of Neurology, University of California, San Francisco, San Francisco, United States, 3C.S. Kubik laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital, Boston, United States, 4Schoo! of Medical Science, Faculty of Medicine, University of New South Wales, and Neuroscience Research Australia, Randwick, Australia, 5Ageing Research Unit, School of Public Health, Imperial College London, London, United Kingdom, 6Centre for Neuroinflammation and Neurodegeneration, Department of Medicine, Imperial College London, London, United Kingdom, 7Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States 

Aims: In parallel to findings with PrP scrapie (PrPSc) prions, misfolded α-synuclein isolated from multiple system atrophy (MSA) patient samples transmit neurological disease to transgenic (Tg) mice following intracerebral inoculation. These findings demonstrate the presence of α-synuclein prions in MSA. While PrPSc prions transmit disease following peripheral exposure to the misfolded protein, similar studies have not been done with MSA patient samples. Here, we assess the transmissibility of α-synuclein prions following peripheral inoculation. 

Methods: Tg mice expressing human α-synuclein with the A53T mutation (M83+/-) were inoculated with brain homogenate prepared from MSA patient samples in the intraperitoneal cavity, hind leg, or tongue. Following inoculation, animals were monitored for the onset of neurological disease, and the brains from sick mice were assessed for the presence of phosphorylated α-synuclein neuropathology and detergent-insoluble α-synuclein aggregates. 

Results: Mice inoculated with MSA patient samples developed severe motor deficits, albeit with a longer incubation period than intracerebral inoculation with the same patient samples. However, mice inoculated with control patient samples did not develop neurological disease by 450 days post inoculation (dpi). In addition, phosphorylated α-synuclein deposition in the brains of sick mice co-localized with p62 and ubiquitin; these aggregates were not seen in the brains of mice inoculated with control patient samples. Further, detergent-insoluble α-synuclein aggregates were isolated from sick mice, whereas these aggregates were not detected in control animals. 

Conclusions: With remarkable similarity to PrPSc prions, α-synuclein prions in MSA patients can be transmitted via peripheral exposure using a rodent model of synucleinopathy. Further studies to assess the transmissibility of this disease are needed.

Tuesday, September 8, 2015

Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism

Terry S. Singeltary Sr.