Skip to main content
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian
  • Log in
  • My Cart

Main menu

  • Home
  • Articles
    • Current
    • Latest Articles
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • Archive
  • Front Matter
  • News
    • For the Press
    • Highlights from Latest Articles
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Purpose and Scope
    • Editorial and Journal Policies
    • Submission Procedures
    • For Reviewers
    • Author FAQ
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Home
Home

Advanced Search

  • Home
  • Articles
    • Current
    • Latest Articles
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • Archive
  • Front Matter
  • News
    • For the Press
    • Highlights from Latest Articles
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Purpose and Scope
    • Editorial and Journal Policies
    • Submission Procedures
    • For Reviewers
    • Author FAQ

New Research In

Physical Sciences

Featured Portals

  • Physics
  • Chemistry
  • Sustainability Science

Articles by Topic

  • Applied Mathematics
  • Applied Physical Sciences
  • Astronomy
  • Computer Sciences
  • Earth, Atmospheric, and Planetary Sciences
  • Engineering
  • Environmental Sciences
  • Mathematics
  • Statistics

Social Sciences

Featured Portals

  • Anthropology
  • Sustainability Science

Articles by Topic

  • Economic Sciences
  • Environmental Sciences
  • Political Sciences
  • Psychological and Cognitive Sciences
  • Social Sciences

Biological Sciences

Featured Portals

  • Sustainability Science

Articles by Topic

  • Agricultural Sciences
  • Anthropology
  • Applied Biological Sciences
  • Biochemistry
  • Biophysics and Computational Biology
  • Cell Biology
  • Developmental Biology
  • Ecology
  • Environmental Sciences
  • Evolution
  • Genetics
  • Immunology and Inflammation
  • Medical Sciences
  • Microbiology
  • Neuroscience
  • Pharmacology
  • Physiology
  • Plant Biology
  • Population Biology
  • Psychological and Cognitive Sciences
  • Sustainability Science
  • Systems Biology

Expanding the prion disease repertoire

Surachai Supattapone
PNAS September 22, 2015 112 (38) 11748-11749; published ahead of print September 1, 2015 https://doi.org/10.1073/pnas.1515143112
Surachai Supattapone
Departments of Biochemistry and Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH 03755
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: supattapone@dartmouth.edu

See related content:

  • Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism
    - Sep 22, 2015
  • Article
  • Info & Metrics
  • PDF
Loading

In 1982, Stanley Prusiner proposed that the infectious agent of transmissible spongiform encephalopathies (TSEs), a group of relatively rare neurodegenerative disorders that includes Creutzfeldt–Jakob disease and scrapie, lacks replicating nucleic acids and instead is composed primarily of a misfolded conformation of the prion protein, which he termed PrPSc (1). Originally, the “prion” hypothesis was met with considerable skepticism because it was difficult to envision how an infectious agent could replicate without a nucleic acid genome. However, a variety of biochemical and genetic experiments subsequently demonstrated the existence of infectious prions (2), eventually fulfilling Koch’s postulates (3). It is now generally accepted that infectious prions replicate through the autocatalytic misfolding of a normal host protein (PrPC) into the PrPSc conformation. In PNAS, Prusiner et al. (4) report findings suggesting that another molecule, α-synuclein, might also act as a prion in a human disease.

Do Prions Cause Diseases Other than TSEs?

In recent years, many researchers have been investigating the intriguing possibility that a variety of other neurodegenerative diseases, including relatively common disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), might also be caused by “prions” composed of misfolded proteins other than PrPSc. Although there is currently no epidemiologic evidence to suggest that either AD or PD has an infectious etiology, it has nonetheless been proposed, on the basis of neuropathological observations in human patients and experiments in cell and animal models, that specific disease-associated proteins such as Aβ, tau, and α-synuclein might also be prions that can spread progressively throughout the brain (5).

Following the model established by prior work on TSEs, the general experimental paradigm used in most of these studies has been to inoculate mice or primates with various inocula containing the candidate misfolded protein and then monitor the animals for the development of neurological symptoms and neuropathology. A realistic assessment of the results of these experiments would indicate that the new candidate prions seem to be much less efficient than PrPSc in causing neurodegeneration in normal hosts. Although all of the new candidate prions can form extensive deposits in brain tissue, this deposition typically does not cause neuronal death unless the host animal is engineered to express a pathogenic mutant protein (6, 7) or very large quantities of misfolded proteins are directly inoculated into a vulnerable brain region (8). Quantitatively, the new candidate prions seem to be over a millionfold less pathogenic than PrPSc, which can induce a transmissible disease when injected in subattomole quantities into nontransgenic hosts (9).Prusiner et al. report striking results that shed light on how α-synuclein may act as a prion in human disease.

The Case for Multiple System Atrophy Prions

Although templated protein misfolding could potentially play a mechanistic role in the progression of non-TSE neurodegenerative diseases, it is unclear what that role might be, given the relative inefficiency of the new candidate prions. Against this backdrop, Prusiner et al. (4) report striking results that shed light on how α-synuclein may act as a prion in human disease. Clinically, the deposition of misfolded α-synuclein in neurons or glial cells is the shared neuropathological characteristic that defines a diverse group of sporadic human neurodegenerative disorders that include PD, dementia with Lewy bodies, pure autonomic failure, and multiple system atrophy (MSA) (10).

Prusiner and his colleagues report that homogenates prepared from the brains of patients with MSA are able induce a disease characterized by motor symptoms in Tg(M83+/−) mice, engineered to express human A53T α-synuclein (4, 11). This disease was accompanied by deposition of insoluble phosphorylated α-synuclein and was transmissible to Tg(M83+/−) mice upon serial passage. In contrast, inoculation of brain homogenates from the brains of PD patients into Tg(M83+/−) mice failed to induce either neurological symptoms or the deposition of insoluble phosphorylated α-synuclein (4). Prusiner et al. (4) also show that MSA, but not PD, brain homogenates could seed the intracellular aggregation of intracellular GFP-tagged A53T α-synuclein in cultured cells. The marked difference in seeding ability between MSA and PD brain homogenates in both assays is probably the most striking and significant aspect of the study. The results are particularly convincing because the investigators included 14 human cases of MSA and 7 cases of PD in their study. It is worth noting that the A53T mutation was originally linked to early onset PD with Lewy bodies in a Greek–Italian family (12), so one might have expected that it should have been easier for this mutant sequence to be seeded by PD brain homogenate than by MSA brain homogenate. The seeding specificity displayed in both the cell culture and animal assays provides compelling support for the hypothesis that α-synuclein prions might play a role in the pathogenesis of MSA. However, by the same reasoning, the results suggest that prions may not exist in PD brain. It is possible that a hypothetical “PD prion strain” might require an unknown experimental condition or host factor, but this specific condition must not be satisfied either in transgenic mice or HEK cells, and must also not be necessary for MSA prion conversion. An immediate practical application of the work of Prusnier et al. (4) is that the HEK cell assay can be used as a diagnostic test to distinguish MSA from PD.

A Few Unresolved Issues

Several issues remain to be resolved to rigorously evaluate the potential role of putative MSA prions in causing human disease. One key issue involves the apparent need to use the pathogenic A53T α-synuclein mutation in both cell and animal assays in order to detect seeding activity in MSA brain. Disturbingly, Prusiner et al. (4) report that inoculation of either MSA or PD prions into transgenic mice expressing WT human α-synuclein failed to induce neurological disease. This result raises the following question: If MSA prions are unable to template the aggregation of WT α-synuclein, are they relevant to the pathogenesis of sporadic disease in normal human brain where only WT, rather than mutant, α-synuclein is present? How might this concern be addressed experimentally? One possible explanation for the negative results with WT α-synuclein is that the transgenic mice used in these studies express α-synuclein exclusively in neurons, whereas in clinical cases of MSA α-synuclein typically forms inclusions within glial cells known as Papp–Lantos bodies. It is possible that, to be susceptible to prion-like conformational change, WT α-synuclein must interact with one or more specific cofactors that are present in glial cells but not neurons [notably, in a similar scenario, WT PrPC requires specific cofactors to convert into PrPSc, but PrP molecules harboring pathogenic mutations can misfold without cofactors (13)]. To test this hypothesis, WT α-synuclein could be expressed in glial cells of transgenic mice by using either an endogenous synuclein promoter or a glial-specific promoter. If a specific component of the glial cell environment were necessary for the seeded conversion of WT α-synuclein, using a glial-specific promoter should allow that to happen.

A second issue involves the apparent lack of neuronal degeneration in symptomatic Tg(M83+/−) mice (4). The lack of neuronal death despite the presence of extensive insoluble phosphorylated α-synuclein deposits in neurons is notable because neurodegeneration is a central feature in the pathogenesis of clinical MSA. It is conceivable that the lack of neurodegeneration in Tg(M83+/−) mice might also be caused by the lack of glial α-synuclein expression, because glial cells might play an auxiliary role in mediating cell death. However, there may be a broader explanation for the lack of cell death in this and other models of human neurodegenerative diseases. It has been generally difficult to induce neuronal degeneration in a variety of rodent models of human disease simply by inducing protein misfolding in neurons. For example, the deposition of Aβ plaques in the brains of mice is not accompanied by cell death (6). Some logical explanations for this dissociation include the following: (i): Rodent neurons may be less susceptible than primate neurons to the effects of misfolded human proteins; (ii) it may take many years (more than the lifespan of a mouse) for neurodegeneration to occur; (iii) the conformations of aggregated proteins being propagated and deposited in these experiments may not be the pathophysiologically relevant (toxic) species; and (iv) neuronal degeneration may be a multifactorial process, and protein misfolding alone may not be sufficient to induce cell death. It is likely that different approaches will eventually be required to faithfully recapitulate neurodegeneration experimentally in model systems.

It will also be important to determine the potency of MSA prions. Prusiner et al. (4) inoculated Tg(M83+/−) mice with the equivalent ∼0.3 mg of MSA brain to induce disease but did not test lower doses. Typically, scrapie can be induced by inoculation of a millionfold lower dose into WT mice. It will be useful to measure the specific infectivity of MSA prions quantitatively by end-point titration for at least two reasons. First, confirmation of high specific infectivity would make it more likely that MSA prions are actually responsible for driving the progression of disease in human patients in a manner similar to PrPSc prions. Second, knowing the specific infectivity of MSA prions will help us assess their biohazard potential, so that appropriate precautions can be taken if necessary to prevent their iatrogenic spread.

In summary, roughly three decades after the seminal discovery of PrPSc, Prusiner and other investigators may be on the verge of expanding the prion disease repertoire to include non-TSE disorders such as MSA. However, critical work still remains to confirm the role of α-synuclein prions in the pathogenesis of neurodegeneration in sporadic MSA, and to identify which other neurodegenerative diseases might also be caused by novel prions. It is likely that continued research in this area will create exciting opportunities for developing targeted diagnostic and therapeutic tools based on the seeded propagation of specific proteins.

Footnotes

  • ↵1Email: supattapone{at}dartmouth.edu.
  • Author contributions: S.S. wrote the paper.

  • The author declares no conflict of interest.

  • See companion article on page E5308.

References

  1. ↵
    1. Prusiner SB
    (1982) Novel proteinaceous infectious particles cause scrapie. Science 216(4542):136–144
    .
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Prusiner SB
    (1998) Prions. Proc Natl Acad Sci USA 95(23):13363–13383
    .
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Deleault NR,
    2. Harris BT,
    3. Rees JR,
    4. Supattapone S
    (2007) Formation of native prions from minimal components in vitro. Proc Natl Acad Sci USA 104(23):9741–9746
    .
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Prusiner SB, et al.
    (2015) Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci USA 112:E5308–E5317
    .
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Walker LC,
    2. Jucker M
    (2015) Neurodegenerative diseases: Expanding the prion concept. Annu Rev Neurosci 38:87–103
    .
    OpenUrlCrossRefPubMed
  6. ↵
    1. Meyer-Luehmann M, et al.
    (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313(5794):1781–1784
    .
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Clavaguera F, et al.
    (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11(7):909–913
    .
    OpenUrlCrossRefPubMed
  8. ↵
    1. Luk KC, et al.
    (2012) Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338(6109):949–953
    .
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Deleault NR, et al.
    (2012) Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions. Proc Natl Acad Sci USA 109(28):E1938–E1946
    .
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Martí MJ,
    2. Tolosa E,
    3. Campdelacreu J
    (2003) Clinical overview of the synucleinopathies. Mov Disord 18(Suppl 6):S21–27
    .
    OpenUrlCrossRefPubMed
  11. ↵
    1. Watts JC, et al.
    (2013) Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci USA 110(48):19555–19560
    .
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Spira PJ,
    2. Sharpe DM,
    3. Halliday G,
    4. Cavanagh J,
    5. Nicholson GA
    (2001) Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr alpha-synuclein mutation. Ann Neurol 49(3):313–319
    .
    OpenUrlCrossRefPubMed
  13. ↵
    1. Noble GP,
    2. Walsh DJ,
    3. Miller MB,
    4. Jackson WS,
    5. Supattapone S
    (2015) Requirements for mutant and wild-type prion protein misfolding in vitro. Biochemistry 54(5):1180–1187
    .
    OpenUrlCrossRefPubMed
View Abstract
PreviousNext
Back to top
Article Alerts
Email Article

Thank you for your interest in spreading the word on PNAS.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Expanding the prion disease repertoire
(Your Name) has sent you a message from PNAS
(Your Name) thought you would like to see the PNAS web site.
Citation Tools
Expanding the prion disease repertoire
Surachai Supattapone
Proceedings of the National Academy of Sciences Sep 2015, 112 (38) 11748-11749; DOI: 10.1073/pnas.1515143112

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Expanding the prion disease repertoire
Surachai Supattapone
Proceedings of the National Academy of Sciences Sep 2015, 112 (38) 11748-11749; DOI: 10.1073/pnas.1515143112
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Mendeley logo Mendeley
Proceedings of the National Academy of Sciences: 116 (8)
Current Issue

Submit

Sign up for Article Alerts

Jump to section

  • Article
    • Do Prions Cause Diseases Other than TSEs?
    • The Case for Multiple System Atrophy Prions
    • A Few Unresolved Issues
    • Footnotes
    • References
  • Info & Metrics
  • PDF

You May Also be Interested in

Several aspects of the proposal, which aims to expand open access, require serious discussion and, in some cases, a rethink.
Opinion: “Plan S” falls short for society publishers—and for the researchers they serve
Several aspects of the proposal, which aims to expand open access, require serious discussion and, in some cases, a rethink.
Image credit: Dave Cutler (artist).
Several large or long-lived animals seem strangely resistant to developing cancer. Elucidating the reasons why could lead to promising cancer-fighting strategies in humans.
Core Concept: Solving Peto’s Paradox to better understand cancer
Several large or long-lived animals seem strangely resistant to developing cancer. Elucidating the reasons why could lead to promising cancer-fighting strategies in humans.
Image credit: Shutterstock.com/ronnybas frimages.
Featured Profile
PNAS Profile of NAS member and biochemist Hao Wu
 Nonmonogamous strawberry poison frog (Oophaga pumilio).  Image courtesy of Yusan Yang (University of Pittsburgh, Pittsburgh).
Putative signature of monogamy
A study suggests a putative gene-expression hallmark common to monogamous male vertebrates of some species, namely cichlid fishes, dendrobatid frogs, passeroid songbirds, common voles, and deer mice, and identifies 24 candidate genes potentially associated with monogamy.
Image courtesy of Yusan Yang (University of Pittsburgh, Pittsburgh).
Active lifestyles. Image courtesy of Pixabay/MabelAmber.
Meaningful life tied to healthy aging
Physical and social well-being in old age are linked to self-assessments of life worth, and a spectrum of behavioral, economic, health, and social variables may influence whether aging individuals believe they are leading meaningful lives.
Image courtesy of Pixabay/MabelAmber.

More Articles of This Classification

  • The future of influenza forecasts
  • Integrating morphology and phylogenomics supports a terrestrial origin of insect flight
  • Squid genomes in a bacterial world
Show more

Related Content

  • Transmission of multiple system atrophy prions
  • Scopus
  • PubMed
  • Google Scholar

Cited by...

  • Potential Pathways of Abnormal Tau and {alpha}-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases
  • Scopus (4)
  • Google Scholar

Similar Articles

Site Logo
Powered by HighWire
  • Submit Manuscript
  • Twitter
  • Facebook
  • RSS Feeds
  • Email Alerts

Articles

  • Current Issue
  • Latest Articles
  • Archive

PNAS Portals

  • Classics
  • Front Matter
  • Teaching Resources
  • Anthropology
  • Chemistry
  • Physics
  • Sustainability Science

Information

  • Authors
  • Editorial Board
  • Reviewers
  • Press
  • Site Map

Feedback    Privacy/Legal

Copyright © 2019 National Academy of Sciences. Online ISSN 1091-6490