PolyQ Prions: Part 1
I
first learned about prions as a kid. I remember being fascinated by this
life-like thing that wasn’t alive. Can't recall the book title, but it
discussed Kuru, mad cow's disease (BSE), vCJD, and Prusiner's work. Prions are
misfolded proteins that cause disease on a mainly structural basis - self
aggregation and propagation lead to cell degeneration and death. Recently,
doing research into Hungtington's Disease (HD) and polyX prions rekindled my
interest.
Prions
are so resilient that they can survive gamma rays. In 1967, physicist Tikvah
Alper demonstrated that the scrapie pathogen could not be eliminated by UV rays,
implying that the pathogenic agent did not possess DNA. Instead, the agent was
eliminated by 237nm wavelength light, reminiscent of lipopolysaccharide complex
inactivation, hinting at a key structural feature.
Stanley
Prusiner won the 1997 Nobel prize for characterising prions as the infectious
agent in neurodegenerative diseases, starting with a seminal paper in 1982.
Susan Lindquist, the matriarch of prion biology, further explored prions as
part of biological processes. Based on yeast studies, students in her lab
designed a statistical model to predict prion-like regions (PLAAC – discussed in a separate post).
Since
then, the prion concept has expanded beyond infectious neurodegenerative
diseases into inherited and sporadic neurodegenerative diseases, and
recently into cancer research. The relentless self-aggregation of prions is also harnessed for bioengineering.
In
exploring the origins of life, the prion-first (or amyloid/protein-first)
hypothesis has been explored (Maury, 2009 – see further readings below). The
key idea is that amyloid conformation can propagate (conformational) information
to other molecules, similar to how RNA/DNA transmits sequential information,
but with greater spontaneity and resilience compared to nucleic acids. Considering
high surface radioactivity and UV radiation in early earth, amongst other
physical and chemical stressors which can eliminate nucleic acids, I think this
is worth thinking about. Experiments have been conducted for this hypothesis,
inspired by the famous Urey-Miller experiment (abiotic origin of life).
Here
I'll summarise the research history of polyQ, focussing on a few seminal
papers. Specific details are discussed in separate posts. Look under 'labels'
in the left side bar (3 lines) for all content related to prions.
Brief
note about definitions: amyloid is the general term for misfolded proteins that
aggregate and propagate, while prions are a subclass of amyloids that are
infectious. Since prion is such a catchy term, a lot of literature use the term
‘prion-like’, so in my posts, I generally don’t make this distinction unless
necessary.
Timeline
1. A Mystery: What is the pathogenic agent behind
scrapie? (+ Kuru, BSE, CJD)
1982 - Prusiner defines prions
Prusiner S. B. (1982). Novel
proteinaceous infectious particles cause scrapie. Science (New York,
N.Y.), 216(4542), 136–144. https://doi.org/10.1126/science.6801762
https://www.nobelprize.org/uploads/2018/06/prusiner-lecture.pdf
Prion
diseases can be genetic, infectious or sporadic, involving modification of the
endogenous cellular prion protein. Normal prion (PrPc)
consists of approx. 200 amino acids. The secondary structure is mainly α-helix,
with minimal ß-sheets. This makes PrPc soluble and degradable by
proteases. PrPc is structurally adaptable in response to external
factors, as shown in the yeast prion studies at Lindquist Lab. PrPc is involved in stress response,
survival, differentiation, proliferation, homeostasis and neuroprotection.
Transmissible forms of prions (scrapie, BSE) and sporadic/genetic forms of prion diseases (CJD, FFI) consist of misfolded prions (PrPsc) that are dominated by B-sheets, becoming insoluble and degradation-resistant. PrPsc self-aggregate and propagate. Crucially, they induce misfolding of normal PrP, transmitting within and across organisms. Although there is no evidence for human-human transmission of inherited/sporadic prion-like diseases, animal models have demonstrated potential transmission via injection of abnormal PrPsc into healthy animals, hinting that iatrogenic routes of human-human transmission are theoretically possible. In vitro cellular studies also demonstrate seeding, nucleation and aggregation.
PolyX prions are structurally similar, but distinct from PrPc. PolyX regions consist of homopolymeric sequences of identical amino acids. Only specific amino acids (or combinations) form prions, most notably glutamine (Q) and asparagine (N). (Prion-like probabilities from PLAAC)
PolyX are encoded by repetitive tracts of DNA, e.g. CAG
repeats in HD. The structural features of PolyX enables them to play a
scaffolding role in normal biological processes. However, above a nucleation
threshold (e.g. usually 35-40), they begin exhibiting prion-like properties, dominated
by ß-sheets, inducing characteristic aggregation and
propagation.
Genomic CAG repeats also have distinct structural
features that cause meiotic instability and intergenerational expansion,
leading to anticipation: an inherited disease becoming more severe and
earlier in onset with each successive generation, and somatic expansion:
continuous CAG expansion throughout an affected individual’s lifetime. This
would be discussed in a separate post.
1991: CAG/PolyQ identified for SBMA:
Established 'polyQ
expansion' concept.
La Spada, A. R., Wilson, E. M.,
Lubahn, D. B., Harding, A. E., & Fischbeck, K. H. (1991). Androgen receptor
gene mutations in X-linked spinal and bulbar muscular atrophy. Nature, 352(6330),
77–79. https://doi.org/10.1038/352077a0
1993: CAG/PolyQ identified for HD: Established polyQ repeats as a
class of neurodegenerative etiology.
The Huntington's Disease
Collaborative Research Group. (1993). A novel gene containing a trinucleotide
repeat that is expanded and unstable on Huntington's disease chromosomes. Cell, 72(6),
971–983. https://doi.org/10.1016/0092-8674(93)90585-e
· · ─ ·✶· ─ · ·
3. Structural Basis (1994–2000) What is the structural basis behind PolyQ neurodegenerative diseases?
1994: Polar Zipper Hypothesis: PolyQ aggregates into polar zippers
in computational and experimental models. Possible structural mechanism for
pathology.
Perutz, M. F., Johnson, T., Suzuki,
M., & Finch, J. T. (1994). Glutamine repeats as polar zippers: their
possible role in inherited neurodegenerative diseases. Proceedings of
the National Academy of Sciences of the United States of America, 91(12),
5355–5358. https://doi.org/10.1073/pnas.91.12.5355
1997: Visual Evidence: First experimental and visual
evidence that polyQ aggregates form amyloid fibrils similar
to scrapie prions.
Scherzinger, E., Lurz, R.,
Turmaine, M., Mangiarini, L., Hollenbach, B., Hasenbank, R., Bates, G. P.,
Davies, S. W., Lehrach, H., & Wanker, E. E. (1997). Huntingtin-encoded
polyglutamine expansions form amyloid-like protein aggregates in vitro and in
vivo. Cell, 90(3), 549–558. https://doi.org/10.1016/s0092-8674(00)80514-0
Perutz
proposed the ‘polar zipper’ mechanism by which polyQ sequences aggregate,
highlighting parallels between polyQ aggregation and PrP aggregation. Perutz
(1996) identified the approximate nucleation threshold number (41, current
consensus approx 35-40). Above the nucleation threshold, polyQ sequences form
insoluble aggregates.
In
Scherzinger et al., electron micrographs reveal fibrillar morphology, similar
to scrapie prions and B-amyloid fibrils in AD. Subcellular fractionation and
ultrasound techniques demonstrate in vivo presence of these structures
in mouse models of HD.
PolyQ form β strands held together by H-bonds between amides. Beyond the nucleation threshold, these H-bonds strengthen and shorten via co-operativity, condensing the structure, and facilitating transformation from α-helices to ß-sheets (later research in the 2000-2010s). The Tsemekhman et al., 2007 computational study demonstrated H-bond co-operativity, with David Baker (of RoseTTAFold fame) as the last author. Buchanen et al., 2014 used 2D infrared spectroscopy to detect spectral frequency shifts indicating H-bond strength changes. Most recently, Bagherpoor Helabad et al., 2024 combined experimental techniques (EM, solid-state NMR, etc.) with molecular dynamic simulations, providing direct structural evidence. Dekker et al., 2025 is another interesting computational study of aggregation.
· · ─ ·✶· ─ · ·
Part 2 and 3 : (separate posts)4.
Differentiation between PolyQ/N
5.
Mechanisms (2007–2015)
6.
Prion Criteria
7.
Intercellular Spread (2014–Present)
8.
Expansion of prion concept to cancer research
· · ─ ·✶· ─ · ·
All
further readings arranged in chronological order.
Further reading (early studies
attempting to identify the unknown pathogenic agent)
Alper, T., Cramp, W. A., Haig, D.
A., & Clarke, M. E. (1967). Does the agent of scrapie replicate without
nucleic acid? Nature, 214(5090), 764–766. https://doi.org/10.1038/214764a0
Gibbs, C. J., Jr, Gajdusek, D. C.,
& Latarjet, R. (1978). Unusual resistance to ionizing radiation of the
viruses of kuru, Creutzfeldt-Jakob disease, and scrapie. Proceedings of
the National Academy of Sciences of the United States of America, 75(12),
6268–6270. https://doi.org/10.1073/pnas.75.12.6268
Further reading (PrP)
Samson, A. O., & Levitt, M.
(2011). Normal modes of prion proteins: From native to infectious
particle. Biochemistry, 50(12), 2243–2248. https://doi.org/10.1021/bi1010514
Ziaunys, M., Sarell, C. J., & Meisl,
G. (2020). Formation of distinct prion protein amyloid fibrils under different
conditions. Scientific Reports, 10, 5272. https://doi.org/10.1038/s41598-020-61663-2
Further reading (PolyX Mechanics)
Chen, S., Ferrone, F. A., &
Wetzel, R. (2002). Huntington's disease age-of-onset linked to polyglutamine
aggregation nucleation. Proceedings of the National Academy of Sciences
of the United States of America, 99(18), 11884–11889. https://doi.org/10.1073/pnas.182276099
Tsemekhman, K., Goldschmidt, L.,
Eisenberg, D., & Baker, D. (2007). Cooperative hydrogen bonding in amyloid
formation. Protein science : a publication of the Protein Society, 16(4),
761–764. https://doi.org/10.1110/ps.062609607
Buchanan, L. E., Carr, J. K.,
Fluitt, A. M., Hoganson, A. J., Moran, S. D., de Pablo, J. J., Skinner, J. L.,
& Zanni, M. T. (2014). Structural motif of polyglutamine amyloid fibrils
discerned with mixed-isotope infrared spectroscopy. Proceedings of the
National Academy of Sciences USA, 111(14), 5796–5801. https://doi.org/10.1073/pnas.1401587111
Bagherpoor Helabad, M., Matlahov,
I., Kumar, R. et al. Integrative determination of atomic
structure of mutant huntingtin exon 1 fibrils implicated in Huntington
disease. Nat Commun 15, 10793 (2024). https://doi.org/10.1038/s41467-024-55062-8
Dekker, M., van der Klok, M. L.,
Van der Giessen, E., & Onck, P. R. (2025). A coarse-grained MD model for
disorder-to-order transitions in polyQ aggregation. Journal of Chemical
Theory and Computation. https://doi.org/10.1021/acs.jctc.5c00384
Further reading (Lindquist Lab)
Alberti, S., Halfmann, R., King,
O., Kapila, A., & Lindquist, S. (2009). A systematic survey identifies
prions and illuminates sequence features of prionogenic proteins. Cell, 137(1),
146–158. https://doi.org/10.1016/j.cell.2009.02.044
Lancaster, A. K., Nutter-Upham, A.,
Lindquist, S., & King, O. D. (2014). PLAAC: A web and command-line
application to identify proteins with prion-like amino acid composition. Bioinformatics, 30(17),
2501–2502. https://doi.org/10.1093/bioinformatics/btu310
Further reading (Prion/amyloid/protein-first
hypothesis)
Lee, D. H., Granja, J. R.,
Martinez, J. A., Severin, K., & Ghadiri, M. R. (1996). A self-replicating
peptide. Nature, 382(6591), 525–528. https://doi.org/10.1038/382525a0
Andras, P., & Andras, C.
(2005). The origins of life—the 'protein interaction world' hypothesis: Protein
interactions were the first form of self-reproducing life and nucleic acids
evolved later as memory molecules. Medical Hypotheses, 64(4),
678–688. https://doi.org/10.1016/j.mehy.2004.11.029
Maury, C. P. J. (2009).
Self-propagating β-sheet polypeptide structures as prebiotic informational
molecular entities: The amyloid world. Origins of Life and Evolution of
Biospheres, 39(2), 141–150. https://doi.org/10.1007/s11084-009-9173-6
Maury, C. P. J. (2015). Origin of
life. Primordial genetics: Information transfer in a pre-RNA world based on
self-replicating β-sheet amyloid conformers. Journal of Theoretical
Biology, 382, 292–297. https://doi.org/10.1016/j.jtbi.2015.07.008
Jheeta, S., &
Chatzitheodoridis, E. (2021). The way forward for the origin of life: Prions
and prion-like molecules first hypothesis. Life, 11(8),
872. https://doi.org/10.3390/life11080872
Pohorille, A., & Maury, C. P.
J. (2025). Origin of life: β-sheet amyloid conformers as the primordial
informational, protometabolic, and membrane-interactive entities. FEBS
Letters. https://doi.org/10.1002/1873-3468.70112
Further reading (Experiments
inspired by Urey-Miller)
Fox, S. W., & Harada, K.
(1958). Thermal copolymerization of amino acids to a product resembling
protein. Journal of the American Chemical Society, 80(11),
2857–2860. https://doi.org/10.1021/ja01545a050
Lee, D. H., Granja, J. R.,
Martinez, J. A., Severin, K., & Ghadiri, M. R. (1996). A self-replicating
peptide. Nature, 382(6591), 525–528. https://doi.org/10.1038/382525a0
Greenwald, J., Friedmann, M. P.,
& Riek, R. (2016). Amyloid aggregates arise from amino acid condensations
under prebiotically plausible conditions. Angewandte Chemie
International Edition, 55(38), 11609–11613. https://doi.org/10.1002/anie.201605321
Rout, S. K., Friedmann, M. P., Riek, R., & Greenwald, J. (2018). A prebiotic template-directed peptide synthesis based on amyloids. Nature Communications, 9, 426. https://doi.org/10.1038/s41467-017-02742-3