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.
PRION 2017 DECIPHERING NEURODEGENERATIVE DISORDERS 


Tuesday, September 8, 2015

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























Terry S. Singeltary Sr.




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