Multiple system atrophy (MSA) patients exhibit progressive loss of autonomic nervous system function that is often combined with a movement disorder similar to Parkinson’s disease (PD). A small protein of unknown function, α-synuclein, accumulates in the brain glial cells of MSA patients. Extracts of these proteins were capable of transmitting neurodegeneration, making MSA α-synuclein the first human prion recognized in decades (1).
An alpha-synuclein deposit characteristic of Parkinson’s disease
Prions are misfolded forms of normal proteins that produce deadly diseases including the spongiform encephalopathies like Kuru, Creutzfeldt-Jakob disease (CJD) and mad cow disease. Prions propagate by a templated chain reaction in which the abnormally shaped molecules force their normal counterparts to assume the same disease-producing conformation. Although they are composed only of protein, prions are transmissible disease agents because they spontaneously seed their own reproduction after they enter a new host cell. The demonstration that MSA is caused by a transmissible prion has important implications for medical practices (1).
Some prion diseases have never been observed to be infectious, but they still threaten human health because they can be transmitted by medical procedures such as blood transfusion, transplants and neurosurgery (2). Detecting prions is challenging (3) which makes efforts to prevent their transmission critical. Changes in food production practices, screening potential blood/tissue donors and using stringent decontamination procedures on neurosurgery equipment have helped mitigate the dangers.
The demonstration MSA is new human prion agent raises some questions. Could efforts to treat MSA using deep brain stimulation pose a risk to transfer α-synuclein prion seeds? Although Parkinson’s disease (PD) patients exhibit some of the same clinical signs and accumulate α-synuclein deposits, the specific form of the protein found in PD patients has not been observe to be self-seeding. Physicians will now be vigilant to differentiate MSA cases from instances of Parkinson’s disease.
Because prions resist inactivation, reusable neurosurgery equipment is subjected extra harsh decontamination procedures. The precautions do minimize the risk of transmitting prion disease agents, but do we have all the possibilities covered? The recognition MSA is a prion disease suggests long-standing standards to prevent transmitting pathologic prions by surgery and other medical interventions warrant periodic review and updating. Other degenerative conditions such as Alzheimer’s disease (AD) produce deposits of proteins including β-amyloid and often α-synuclein. Could one or more of these proteins act as prions under the right set of circumstances? Have we accidentally transmitted AD through surgery, transplants and blood transfusions as was done with CJD? Recent studies of deceased recipients of growth hormone obtained from human cadavers suggest β-amyloid like that found in AD patients may have been seeded along with CJD by these treatments (2). All therapeutic use of growth hormone harvested from cadavers was halted after the threat of CJD transmission was recognized. Only a small number of cadaveric growth hormone recipients have been studied to date and only amyloid deposits, not the full suite of AD pathology, have been observed in their brains. However, while these unfortunate subjects did not exhibit classic AD, extensive β-amyloid deposits are inimical to neuronal cell function and seriously impede brain perfusion. Given sufficient time this self-spreading pathology may have ultimately expanded to produce debilitating vascular failure and dementia. The possibility that this β-amyloid brain pathology was seeded by intramuscular injections of hormone preparations is extremely troubling.
Heavy beta-amyloid deposition in the brain blood vessels of an AD patient
AD patients accumulate a diverse spectrum of β-amyloid molecules (2). Whether all are equally toxic is not clear, but not all amyloids are transmissible (2). In addition, while α-synuclein protein is accumulated in both MSA and PD, the specific molecular forms present in the two diseases exhibit different seeding potential. Experiments revealed the form found in MSA patients is a transmissible prion, while the other type present in PD did not seed neurodegeneration (1). In essence each α-synuclein protein type is its own unique story and precisely how they mis-fold determines whether or not they act as prions. The known physical heterogeneity of β-amyloid molecules found in AD patients suggests some could be comparatively benign while others might be readily transmissible. At the moment some data suggests AD amyloids are capable of prion-like seeding (2), but we are unable to conclude if current medical practices are promoting their dissemination. Perhaps AD researchers seeking to understand the factors dictating risk for dementia will examine patient profiles for histories of blood transfusion or surgery.
Past experience with mad cow disease and vCJD outbreaks reveals that prion diseases can pose swiftly arising menaces to animal and human health. The recognition of a new human prion disease coupled with the remarkable functional diversity exhibited by these agents suggests sorting out the risks of disseminating self-seeding rogue proteins through medical practices will be challenging.
(1) S. B. Prusiner et al. 2015. Evidence for α-Synuclein Prions Causing Multiple System Atrophy in Humans with Parkinsonism. Proceedings of the National Academy of Sciences of the United States of America. 112(38):E5308-E5317. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586853/
(2) J. Collinge. 2016. Mammalian Prions and Their Wider Relevance in Neurodegenerative Diseases. Nature 539:217-226, 9 November 2016. http://www.nature.com/nature/journal/v539/n7628/full/nature20415.html
(3) K. Servick. 2016. New Blood Tests Make Strides in detecting Prion Disease. Science, 23 December 2016. http://science.sciencemag.org/content/354/6319/1512.full