Hammarström Lab

members of Hammarström lab, Linköping University
Steve Nyström

We are interested in protein misfolding, amyloid formation and disease, both on the molecular level and in the cellular perspective.

The toxic mechanism of misfolded aggregation intermediates inducing nerve degeneration is largely unknown, and this understanding it is clearly a future goal for our research.

Our objective is to inhibit the formation of the toxic species utilizing different approaches including small-molecule binding and interections with molecular chaperones. A special laboratory for prion research was opened in October of 2005 at LiU for the Hammarstrom research group.

Amyloid plaque in brain tissue.

Research
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Introduction

Our research covers a broad span of proteins, misfolding mechanisms, and chaperones.

We work with a number of proteins prone to misfolding:

• Prion protein (PrP)- associated with the transmissible spongiform encephalopathies (TSE)
• Amyloid-beta (Aβ) - associated with Alzheimer´s disease
• Tau-associated with Alzheimer’s disease and several Tauopathies, eg PSP and CBD
• Transthyretin - associated with familial amyloidotic polyneuropathy (Skelleftesåsjukan)
• Insulin - associated with fibril formation during biotechnological production
• Lysozyme - associated with hereditary non-neuropathic systemic amyloidosis
and the molecular chaperones:

• BiP (Hsp70)
• GroEL (Hsp60)
• GroES (Hsp10) and other HSP10 chaperones
and fluorescent proteins:

• e-GFP
• e-CFP
• e-YFP
• mNeonGreen

We also work with the fly Drosophila melanogaster as research model for neurodegenerative disease, typically animals expressing Aβ and Tau.

Microscope images from Drosophila melanogaster models of Alzheimers disease. The Alzheimer associated protein Aβ has been expressed in different cell types in the central nervous system of the fly and formed amyloid. The amyloid is labled with green pFTAA. Image from Jonson et al Cell Chemical Biology 2018 https://www.sciencedirect.com/science/article/pii/S2451945618301089

The basis for selective vulnerability of certain cell types for misfolded proteins in neurodegenerative diseases is largely unknown. This knowledge is crucial for understanding disease progression in the CNS. Cell specific expression of human Aβ1-42 associated with Alzheimer’s disease in Drosophila neurons resulted in concentration dependent severe neurodegenerative phenotypes, and intraneuronal ring-tangle like aggregates with immature fibril properties. Unexpectedly, expression of Aβ1-42 from a pan-glial driver produced a mild phenotype despite massive brain load of Aβ1-42 aggregates, even higher than in the strongest neuronal driver. Glial cells formed more mature fibrous aggregates, morphologically distinct from aggregates found in neurons, and was mainly extracellular. Our findings implicate that Aβ1-42 cytotoxicity is both cell and aggregate morphotype dependent.

Molecular chaperones

It is now well accepted that misfolded proteins are severely detrimental to the cell. Evidence for this can be found within every cell from E. Coli to dolphins - in the absolutely vital machinery of the molecular chaperones.

Molecular chaperones constitute a natural defense against misfolded proteins. Chaperones can bind and sequester misfolded proteins, stretch them apart to provide a new chance for productive folding or present the misfolded protein to the degradation machinery.

We have shown that the molecular chaperones BiP (Hsp 70) and the bacterial chaperonin GroEL/ES (Hsp 60/10) recognize partially folded substrate proteins (a.k.a. clients) and remodel their structure.

Partially folded proteins are structurally plastic and can in the absence of chaperones result in aberrant aggregation (misfolding). Chaperones can correct misfolded protein structure through binding induced unfolding and provide a new chance for correct folding.

We have shown that Hsp10, albeit small, is potent as an unfoldase and a protein folding guide and also as inhibitor of protein amyloid formation in the test tube.


Misfolding diseases
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Misfolding Diseases

In recent years it has become evident that impaired protein folding plays a key role in a wide variety of diseases.

There are considerable overlaps between these categories and in many cases, it is not clear which of the mechanisms that are the dominating cause of pathology. It is therefore important to have a holistic view of the folding and misfolding areas to understand the molecular basis underlying these diseases.

Common denominators for these proteins are: Aberrant folding, partially folded intermediates, conformational plasticity and protein aggregation.

Amyloid disease

The amyloid diseases is a part of a larger group of conformational diseases, many of which are termed misfolding diseases. This group includes for example devastating diseases such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.

Neurodegeneration is associated with amyloid diseases of the central nervous system, and most often the direct cause of symptoms. It is not known how neurodegeneration commences following misfolding of these proteins and many are the suggestions as of which of the multitude of misfolded self-assembled protein aggregates are the most toxic species.

It is likely that neurons are particularly sensitive to this type of proteinaceous toxins. Part of our research is focused on addressing this question. This is done by combining conformation sensitive, fluorescent, amyloid targeting probes that can be used both in the test tube and on tissue sections for microscopy. We address the test tube samples with biophysical analysis and compare disease properties of different amyloid conformations in animal models or in real patient samples displaying the same amyloid conformations, determined by fluorescence microscopy.

Conformation sensitive fluorescent probes can be used to detect amyloid and discriminate between different types of amyloid within one amyloid deposit. Small changes in the chemical structure of the probes modulate their binding. Image adapted from Zhang et al Journal of Medicinal Chemistry 2019 https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01681

Using conformation sensitive fluorescence probe and a range of fluorescence imaging techniques we can delineate differences in amyloid plaques with high resolution and specificity. Image adapted from Nyström et al Journal of visualized experiments 2017 https://www.jove.com/video/56279/imaging-amyloid-tissues-stained-with-luminescent-conjugated

Systemic amyloidosis

Amyloids can be found in virtually any organ of the body and over 35 different proteins are known to form amyloid in humans.

Familial Amyloidotic Polyneuropathy (FAP), also known as Skellefteåsjukan, is caused by amyloid formation of Transthyretin (TTR). FAP is hereditary and carriers of the disease associated mutant TTR will invariably come down with the disease. Successful basic research has paved the way for the treatment of this disease by stabilizing the culprit protein, the mutated TTR, and thereby preventing it from misfolding into amyloid.

This and other successful treatment strategies has proven that targeting protein misfolding can prevent or cure amyloid diseases.

Many different protein cause amyloid formation and disease in the human body. However, amyloid steming from the same protein does not always adopt the same amyloid structure. This conformational polymorphism is one of our research topics. Image from Fändrich et al, Journal of Internal Medicine 2018 https://onlinelibrary.wiley.com/doi/full/10.1111/joim.12732

Infectious protein misfolding

The prion diseases Creutzfeldt-Jakob’s disease and Bovine Spongiform Encephalopathy (Mad cow disease) are often associated with amyloid deposition. The term Prion is an abbreviation for PRotein Infectious ONly. Prions, in the classic sense, are protein infectious agents composed of the prion protein PrP. However, the debate is ongoing regarding prion properties also exhibited by amyloid assemblies comprised of other proteins.

The prion protein particle was the first example of an infectious agent that lacks nucleic acid, as opposed to conventional infectious agents such as parasites, bacteria or viruses. Prions cause a variety of diseases in humans and animals including bovine spongiform encephalopathy (BSE) or mad cow disease, Creutzfeldt-Jakob disease (in humans), Chronic wasting disease (in deer and elk) and scrapie (in sheep). Collectively prion diseases are in medical terms named transmissible spongiform encephalopathies or TSE´s due to the transmissibility of the diseases and the pathological feature of microvacuole formation in affected areas of the brain.

A dramatic feature of the transmissible spongiform encephalopathies, TSEs, is the rapid and efficient neuronal degeneration process. Misfolding of the prion protein (PrP) is a crucial step in these diseases. Here, the PrP misfolding process entails the conversion of a helical protein to a largely insoluble β–sheet rich state.

But, how can a misfolding process be infectious? The novel and controversial concept of the prion hypothesis is the propagation of protein conformations through structure based templated folding presented by Stanley Prusiner and is replicated in vitro (see Figure below).

PrP - The full-length soluble domain of mature human PrP protein is composed of 209 amino acids (res. 23-231) and is, in the natively folded PrPC form, folded into two domains. The N-terminal unstructured domain comprising the initial 90 residues has very high flexibility and affinity for Cu2+. The C-terminal globular domain folds into four helices and two short β–strands. The structure of the disease causing and infectious misfolded PrPSC particle is not known in detail due to the insolubility of the protein. PrPSC adopts a stable oligomeric structure with a large amount of β–sheet structure. Prion strains appear to be encoded in the PrPSC structure.

The prion protein can convert into its disease causing amyloid conformation both through a sporadic route and by templated seeding by adding a small fraction already formed amyloids. The spontaneous, unseeded reaction is significantly slower than the seeded reaction. Image adapted from Nyström et al, Journal of Biological Chemistry 2012 http://www.jbc.org/content/287/31/25975.long

Prion disease in mammals

Prion diseases, also termed TSEs (transmissible spongiform encephalopathy) are known to afflict a large number of mammals. The disease is mediated either by sporadic events of misfolding of the endogenously expressed PrP, or by transmission of preformed, misfolded prion particles from a source outside of the host.

BSE in cattle, Scrapie in sheep, MSE in mink and Chronic wasting disease in wild cervids has been known for several decades. More recently, prion disease has been discovered in dromedary camels in North Africa, demonstrating again the wide spread of prion disease among mammalian species.

The three-dimensional fold of native PrP from a wide range of mammals is well conserved. However, the amino acid sequence can vary. There are a number of single nucleotide polymorphisms (SNPs) that are hypothetically protective against infection by prion disease. Dogs and pigs appear resistant to prion disease, while human, cat and cow all are susceptible to prion infection.

We have shown that, although being resistant to prion disease, both dog PrP and pig PrP readily form amyloid fibrils in the test tube and the resulting fibrils are capable of enhancing amyloid fibril formation of any of the PrP sequences we tested, regardless of species origin, prion susceptible or resistant.

We study prion protein sequences from several different mammals and how their similarities and differences dictate their ability to form amyloid and interfere with each other. Image adapted from Nyström and Hammarström Scientific Report 2015 https://www.nature.com/articles/srep10101

One intriguing feature about prion biology is the strain phenomenon and how it is coupled to a species barrier that moderates which species can infect and be infected by which.

Although very similar in native three-dimensional structure, PrP can misfold into numerous misfolded states and thereby cause disease with different clinical attributes as well as histologic lesion profiles. Often, the strain rather than the amino acid sequence dictates the course of disease, as well as intra- and inter species transmission. When a prion strain is transmitted from one species to another, it can reside in, and transmit between individuals of the new host species without causing clinical disease, for several generations before it eventually has adapted to its new host. The novel, adapted strain can then cause disease with different clinical symptoms than were seen in the original donor species.

Prions in wild animals has been on our agenda for some time. Prions strains rather than amino acid sequence dictate their infectivity. Prions are known to be able to adapt to novel species, generating new infectious strains.

Since 2016 it has been known that Chronic Wasting disease is present in Europe, after the discovery of the disease in a reindeer in Norway. As of March 2019 the disease is also a fact in Sweden. Already at this early stage of investigation (May 2019) there are strong indications that the CWD prion strains found in Scandinavia are different from those found in North America.

We run a BSL3 lab dedicated to the studies of prions, specializing in experiments in the intersection between recombinant proteins and tissue samples.

Molecular chaperones
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Molecular chaperones

It is now well accepted that misfolded proteins are severely detrimental to the cell. Evidence for this can be found within every cell from E. Coli to dolphins - in the absolutely vital machinery of the molecular chaperones.

Molecular chaperones constitute a natural defense against misfolded proteins. Chaperones can bind and sequester misfolded proteins, stretch them apart to provide a new chance for productive folding or present the misfolded protein to the degradation machinery.
We have shown that the molecular chaperones BiP (Hsp 70) and the bacterial chaperonin GroEL/ES (Hsp 60/10) recognize partially folded substrate proteins (a.k.a. clients) and remodel their structure. Partially folded proteins are structurally plastic and can in the absence of chaperones result in aberrant aggregation (misfolding). Chaperones can correct misfolded protein structure through binding induced unfolding and provide a new chance for correct folding. We have shown that Hsp10, albeit small, is potent as an unfoldase and a protein folding guide and also as inhibitor of protein amyloid formation in the test tube.

Related
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Contact
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Publications
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Published Articles

  • Photonic amyloids. Hammarström. P. Nature Photonics, 13, 442–444 (2019). nature.com
  • Impact of N-glycosylation site variants during human PrP aggregation and fibril nucleation. Mishra R, Elgland M, Begum A, Fyrner T, Konradsson P, Nyström S, Hammarström P. Biochim Biophys Acta Proteins Proteom. 2019 Mar 30. pii: S1570-9639(19)30062-7. doi: 0.1016/j.bbapap.2019.03.010. Pubmed
  • Pyroglutamation of amyloid-βx-42 (Aβx-42) followed by Aβ1-40 deposition underlies plaque polymorphism in progressing Alzheimer's disease pathology. Michno W, Nyström S, Wehrli P, Lashley T, Brinkmalm G, Guerard L, Syvänen S, Sehlin D, Kaya I, Brinet D, Nilsson KPR, Hammarström P, Blennow K, Zetterberg H, Hanrieder J. J Biol Chem. 2019 Feb 27. pii: jbc.RA118.006604. doi: 10.1074/jbc.RA118.006604. Pubmed
  • Phenolic Bis-styrylbenzo[ c]-1,2,5-thiadiazoles as Probes for Fluorescence Microscopy Mapping of Aβ Plaque Heterogeneity. Zhang J, Konsmo A, Sandberg A, Wu X, Nyström S, Obermüller U, Wegenast-Braun BM, Konradsson P, Lindgren M, Hammarström P. J Med Chem. 2019 Feb 28;62(4):2038-2048. doi: 10.1021/acs.jmedchem.8b01681. Epub 2019 Feb 13. Pubmed
  • Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins. Zhang J, Wang J, Sandberg A, Wu X, Nyström S, LeVine H 3rd, Konradsson P, Hammarström P, Durbeej B, Lindgren M. Chemphyschem. 2018 Nov 19;19(22):3001-3009. doi: 10.1002/cphc.201800823. Epub 2018 Oct 8. Pubmed
  • Luminescent-Conjugated Oligothiophene Probe Applications for Fluorescence Imaging of Pure Amyloid Fibrils and Protein Aggregates in Tissues. Nilsson KPR, Lindgren M, Hammarström P. Methods Mol Biol. 2018;1779:485-496. doi: 10.1007/978-1-4939-7816-8_30. Pubmed
  • Multimodal Chemical Imaging of Amyloid Plaque Polymorphism Reveals Aβ Aggregation Dependent Anionic Lipid Accumulations and Metabolism. Michno W, Kaya I, Nyström S, Guerard L, Nilsson KPR, Hammarström P, Blennow K, Zetterberg H, Hanrieder J. Anal Chem. 2018 Jul 3;90(13):8130-8138. doi: 10.1021/acs.analchem.8b01361. Epub 2018 Jun 19. Pubmed
  • Aggregated Aβ1-42 Is Selectively Toxic for Neurons, Whereas Glial Cells Produce Mature Fibrils with Low Toxicity in Drosophila. Jonson M, Nyström S, Sandberg A, Carlback M, Michno W, Hanrieder J, Starkenberg A, Nilsson KPR, Thor S, Hammarström P. Cell Chem Biol. 2018 May 17;25(5):595-610.e5. doi: 10.1016/j.chembiol.2018.03.006. Epub 2018 Apr 12. Pubmed
  • Detection and Imaging of Aβ1-42 and Tau Fibrils by Redesigned Fluorescent X-34 Analogues. Zhang J, Sandberg A, Konsmo A, Wu X, Nyström S, Nilsson KPR, Konradsson P, LeVine H 3rd, Lindgren M, Hammarström P. Chemistry. 2018 May 17;24(28):7210-7216. doi: 10.1002/chem.201800501. Epub 2018 Apr 26. Pubmed
  • Generation of novel neuroinvasive prions following intravenous challenge. Aguilar-Calvo P, Bett C, Sevillano AM, Kurt TD, Lawrence J, Soldau K, Hammarström P, Nilsson KPR, Sigurdson CJ. Brain Pathol. 2018 Nov;28(6):999-1011. doi: 10.1111/bpa.12598. Epub 2018 Jul 5. Pubmed
  • Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis. Khodaparast L, Khodaparast L, Gallardo R, Louros NN, Michiels E, Ramakrishnan R, Ramakers M, Claes F, Young L, Shahrooei M, Wilkinson H, Desager M, Mengistu Tadesse W, Nilsson KPR, Hammarström P, Aertsen A, Carpentier S, Van Eldere J, Rousseau F, Schymkowitz J. Nat Commun. 2018 Feb 28;9(1):866. doi: 10.1038/s41467-018-03131-0. Pubmed
  • Amyloid fibril polymorphism: a challenge for molecular imaging and therapy. Fändrich M, Nyström S, Nilsson KPR, Böckmann A, LeVine H 3rd, Hammarström P. J Intern Med. 2018 Mar;283(3):218-237. doi: 10.1111/joim.12732. Epub 2018 Feb 19. Pubmed
  • Binding of polythiophenes to amyloids: structural mapping of the pharmacophore. Schuetz AK, Hornemann S, Wälti MA, Greuter L, Tiberi C, Cadalbert R, Ganter M, Riek R, Hammarström P, Nilsson KPR, Böckmann A, Aguzzi AA, Meier BH. ACS Chem Neurosci. 2017 Nov 27. doi: 10.1021/acschemneuro.7b00397. Pubmed
  • Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease. Rasmussen J, Mahler J, Beschorner N, Kaeser SA, Häsler LM, Baumann F, Nyström S, Portelius E, Blennow K, Lashley T, Fox NC, Sepulveda-Falla D, Glatzel M, Oblak AL, Ghetti B, Nilsson KPR, Hammarström P, Staufenbiel M, Walker LC, Jucker M. Proc Natl Acad Sci U S A. 2017 Nov 20. pii: 201713215. doi: 10.1073/pnas.1713215114. Pubmed
  • Imaging Amyloid Tissues Stained with Luminescent Conjugated Oligothiophenes by Hyperspectral Confocal Microscopy and Fluorescence Lifetime Imaging. Nyström S, Bäck M, Nilsson KPR, Hammarström P. J Vis Exp. 2017 Oct 20;(128). doi: 10.3791/56279. Pubmed
  • trans-Stilbenoids with Extended Fluorescence Lifetimes for the Characterization of Amyloid Fibrils Jun Zhang, Alexander Sandberg, Xiongyu Wu, Sofie Nyström, Mikael Lindgren, Peter Konradsson, and Per Hammarström ACS Omega, 2017, 2 (8), pp 4693–4704 DOI: 10.1021/acsomega.7b00535 Full text at ACS Omega
  • Seed-dependent templating of murine AA amyloidosis. Nyström S, Vahdat Shariat Panahi A, Nilsson KPR, Westermark P, Westermark GT, Hammarström P, Lundmark K. Amyloid. 2017 Mar;24(sup1):140-141. doi: 10.1080/13506129.2017.1290599. Pubmed
  • Establishing and validating the fluorescent amyloid ligand h-FTAA (heptamer formyl thiophene acetic acid) to identify transthyretin amyloid deposits in carpal tunnel syndrome. Hahn K, Nilsson KPR, Hammarström P, Urban P, Meliss RR, Behrens HM, Krüger S, Röcken C. Amyloid. 2017 Jun;24(2):78-86. doi: 10.1080/13506129.2017.1316711. Epub 2017 Apr 23. Pubmed
  • Nanoscale Structure and Spectroscopic Probing of Aβ1-40 Fibril Bundle Formation. Psonka-Antonczyk KM, Hammarström P, Johansson LB, Lindgren M, Stokke BT, Nilsson KP, Nyström S. Front Chem. 2016 Nov 22;4:44. Pubmed
  • De novo design of a biologically active amyloid  Gallardo R, Ramakers M, De Smet F, Claes F, Khodaparast L, Khodaparast L, Couceiro JR, Langenberg T, Siemons M, Nyström S, Young LJ, Laine RF, Young L, Radaelli E, Benilova I, Kumar M, Staes A, Desager M, Beerens M, Vandervoort P, Luttun A, Gevaert K, Bormans G, Dewerchin M, Van Eldere J, Carmeliet P, Vande Velde G, Verfaillie C, Kaminski CF, De Strooper B, Hammarström P, Nilsson KP, Serpell L, Schymkowitz J, Rousseau F. Science. 2016 Nov 11;354(6313). pii: aah4949. Pubmed
  • Novel trans-Stilbene-based Fluorophores as Probes for Spectral Discrimination of Native and Protofibrillar Transthyretin. Campos RI, Wu X, Elgland M, Konradsson P, Hammarström P. ACS Chem Neurosci. 2016 Jul 20;7(7):924-40. doi: 10.1021/acschemneuro.6b00062. Epub 2016 May 19. Pubmed
  • Differential conformational modulations of MreB folding upon interactions with GroEL/ES and TRiC chaperonin components. Moparthi SB, Carlsson U, Vincentelli R, Jonsson BH, Hammarström P, Wenger J. Sci Rep. 2016 Jun 22;6:28386. doi: 10.1038/srep28386. Pubmed
  • (11)C and (18)F Radiolabeling of Tetra- and Pentathiophenes as PET-Ligands for Amyloid Protein Aggregates. Nordeman P, Johansson LB, Bäck M, Estrada S, Hall H, Sjölander D, Westermark GT, Westermark P, Nilsson L, Hammarström P, Nilsson KP, Antoni G. ACS Med Chem Lett. 2016 Feb 18;7(4):368-73. doi: 10.1021/acsmedchemlett.5b00309. eCollection 2016 Apr 14. Pubmed
  • Establishing the fluorescent amyloid ligand h-FTAA for studying human tissues with systemic and localized amyloid. Sjölander D, Röcken C, Westermark P, Westermark GT, Nilsson KP, Hammarström P. Amyloid. 2016 Mar 17:1-11. [Epub ahead of print] Pubmed
  • Protein aggregation as an antibiotic design strategy Bednarska NG, Van Eldere J, Gallardo R, Ganesan A, Ramakers M, Vogel I, Baatsen P, Staes A, Goethals M, Hammarström P, Nilsson KP, Gevaert K, Schymkowitz J, Rousseau F. Mol Microbiol. 2015 Nov 12. doi: 10.1111/mmi.13269. [Epub ahead of print] Pubmed
  • Pathological, biochemical, and biophysical characteristics of the transthyretin variant Y114H (p.Y134H) explain its very mild clinical phenotype. Sekijima Y, Campos RI, Hammarström P, Nilsson KP, Yoshinaga T, Nagamatsu K, Yazaki M, Kametani F, Ikeda SI.J Peripher Nerv Syst. 2015 Aug 26. doi: 10.1111/jns.12143. [Epub ahead of print] Pubmed
  • Structure-based drug design identifies polythiophenes as antiprion compounds Herrmann US, Schütz AK, Shirani H, Huang D, Saban D, Nuvolone M, Li B, Ballmer D, Åslund AKO, Mason JJ, Rushing E, Budka H, Nyström S, Hammarström P, Böckmann A, Caflisch A, Meier BH, Nilsson KPR, Hornemann S, Aguzzi Sci Transl Med. 2015 Aug 5;7(299):299ra123. doi: 10.1126/scitranslmed.aab1923 Pubmed
  • Porcine Prion Protein Amyloid Hammarström P, Nyström S. Prion. 2015 Jul 4;9(4):266-277 Pubmed
  • Systematic Aβ Analysis in Drosophila Reveals High Toxicity for the 1-42, 3-42 and 11-42 Peptides, and Emphasizes N- and C-Terminal Residues Jonson M, Pokrzywa M, Starkenberg A, Hammarstrom P, Thor S.PLoS One. 2015 Jul 24;10(7):e0133272. doi: 10.1371/journal.pone.0133272. eCollection 2015 Pubmed
  • Considerably Unfolded Transthyretin Monomers Preceed and Exchange with Dynamically Structured Amyloid Protofibrils. Groenning M, Campos RI, Hirschberg D, Hammarström P, Vestergaard B. Sci Rep. 2015 Jun 25;5:11443. doi: 10.1038/srep11443. Pubmed
  • Generic amyloidogenicity of mammalian prion proteins from species susceptible and resistant to prions Nyström S, Hammarström P Sci Rep 2015, Article number: 10101 Doi:10.1038/srep10101 Pubmed
  • Sensitive and rapid assessment of amyloid by oligothiophene fluorescence in subcutaneous fat tissue. Sjölander D, Bijzet J, Hazenberg BP, Nilsson KP, Hammarström P. Amyloid. 2015 Mar;22(1):19-25. doi: 10.3109/13506129.2014.984063 Pubmed
  • Aβ seeds resist inactivation by formaldehyde. Fritschi SK, Cintron A, Ye L, Mahler J, Bühler A, Baumann F, Neumann M, Nilsson KP, Hammarström P, Walker LC, Jucker M. Acta Neuropathol. 2014 Oct;128(4):477-84 Pubmed
  • Multimodal fluorescence microscopy of prion strain specific PrP deposits stained by thiophene-based amyloid ligands Magnusson K, Simon R, Sjölander D, Sigurdson CJ, Hammarström P, Nilsson KP (2014) Prion May 15;8(3) Pubmed
  • Direct visualization of HIV-enhancing endogenous amyloid fibrils in human semen Usmani SMi, Zirafi O, Müller A, Sandi-Monroy NL, Yadav JK, Meier C, Weil T, Roan NR, Greene WC, Walther P, Nilsson KPR, Hammarström P, Wetzel R, Pilcher CD, Gagsteiger F, Fändrich M, Kirchhoff F, Münch J (2014) Nat Commun Apr 1;5:3508 Pubmed
  • Is the prevalent human prion protein 129M/V mutation a living fossil from a Paleolithic panzootic superprion pandemic? Nyström S, Hammarström P. (2014) Prion. 2014 Jan 8;8(1): 2-10 Pubmed
  • Transient conformational remodeling of folding proteins by GroES—individually and in concert with GroEL Moparthi SB, Sjölander D, Villebeck L, Jonsson BH, Hammarström P, Carlsson C. (2014) J Chem Biol Jan 7(1):1-15 Pubmed
  • Amyloid Beta1-40-Induced Astrogliosis and the Effect of Genistein Treatment in Rat: A Three-Dimensional Confocal Morphometric and Proteomic Study Bagheri M, Rezakhani A, Nyström S, Turkina MV, Roghani M, Hammarström P, Mohseni S (2013) PLoS One, Oct 9;8(10):e76526 Pubmed
  • Seeded strain-like transmission of β-amyloid morphotypes in APP transgenic mice. Heilbronner G, Eisele YS, Langer F, Kaeser SA, Novotny R, Nagarathinam A, Aslund A, Hammarström P, Nilsson KP, Jucker M. (2013) EMBO Rep, 30;14(11):1017-22. PubMed
  • Evidence for Age-Dependent in Vivo Conformational Rearrangement within Aβ Amyloid Deposits, Nyström S., Psonka-Antonczyk K.M., Ellingsen P.G., Johansson L.B., Reitan N., Handrick S., Prokop S., Heppner F.L., Wegenast-Braun B.M., Jucker M., Lindgren M., Stokke B.T., Hammarström P., Nilsson K.P. (2013), ACS Chemical Biology, 8 (6), 1128–1133 PubMed      Video "The plaque"
  • Spectral discrimination of cerebral amyloid lesions after peripheral application of luminescent conjugated oligothiophenes,Wegenast-Braun, B. M., Skodras, A., Bayraktar, G., Mahler, J., Fritschi, S. K., Klingstedt, T., Mason, J. J., Hammarstrom, P., Nilsson, K. P., Liebig, C., and Jucker, M. (2012) The American journal of pathology 181, 1953-1960. PubMed
  • Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand, Arja, K., Sjolander, D., Aslund, A., Prokop, S., Heppner, F. L., Konradsson, P., Lindgren, M., Hammarstrom, P., Aslund, K. O., and Nilsson, K. P. (2013),Macromolecular rapid communications, 14;34(9):723-30. Pubmed
  • Multiple substitutions of methionine 129 in human prion protein reveal its importance in the amyloid fibrillation pathway, Nystrom, S., Mishra, R., Hornemann, S., Aguzzi, A., Nilsson, K. P., and Hammarstrom, P. (2012) The Journal of biological chemistry 287, 25975-25984. PubMed
  • Derivatization of a Bioorthogonal Protected Trisaccharide Linker-Toward Multimodal Tools for Chemical Biology,Fyrner, T., Magnusson, K., Nilsson, K. P., Hammarstrom, P., Aili, D., and Konradsson, P. (2012) Bioconjugate chemistry 23 (6), 1333–1340. PubMed
  • A pentameric luminescent-conjugated oligothiophene for optical imaging of in vitro-formed amyloid fibrils and protein aggregates in tissue sections,Nilsson, K. P., Lindgren, M., and Hammarstrom, P. (2012) Methods Mol Biol 849, 425-434. PubMed
  • Polythiophenes inhibit prion propagation by stabilizing prion protein (PrP) aggregates, Margalith, I., Suter, C., Ballmer, B., Schwarz, P., Tiberi, C., Sonati, T., Falsig, J., Nystrom, S., Hammarstrom, P., Aslund, A., Nilsson, K. P., Yam, A., Whitters, E., Hornemann, S., and Aguzzi, A. (2012) The Journal of biological chemistry 287, 18872-18887. PubMed
  • Power tools for Alzheimer's disease - an electrochemical preamp for Abeta, Zetterberg, H., and Hammarstrom, P. (2012) Journal of neurochemistry. PubMed
  • Nanoscopic and photonic ultrastructural characterization of two distinct insulin amyloid States, Psonka-Antonczyk, K. M., Duboisset, J., Stokke, B. T., Zako, T., Kobayashi, T., Maeda, M., Nystrom, S., Mason, J., Hammarstrom, P., Nilsson, K. P., and Lindgren, M. (2012) International journal of molecular sciences 13, 1461-1480. Pubmed
  • Curcumin promotes A-beta fibrillation and reduces neurotoxicity in transgenic Drosophila, Caesar, I., Jonson, M., Nilsson, K. P., Thor, S., and Hammarstrom, P. (2012) PloS one 7, e31424. Pubmed
  • Cell interaction study of amyloid by using luminescent conjugated polythiophene: implication that amyloid cytotoxicity is correlated with prolonged cellular binding, Zako, T., Sakono, M., Kobayashi, T., Sorgjerd, K., Nilsson, K. P., Hammarstrom, P., Lindgren, M., and Maeda, M. (2012) Chembiochem 13, 358-363. PubMed
  • Synthesis of a library of oligothiophenes and their utilization as fluorescent ligands for spectral assignment of protein aggregates, Klingstedt, T., Aslund, A., Simon, R. A., Johansson, L. B., Mason, J. J., Nystrom, S., Hammarstrom, P., and Nilsson, K. P. (2011) Organic & biomolecular chemistry 9, 8356-8370. PubMed
  • Observations in APP bitransgenic mice suggest that diffuse and compact plaques form via independent processes in Alzheimer's disease, Lord, A., Philipson, O., Klingstedt, T., Westermark, G., Hammarstrom, P., Nilsson, K. P., and Nilsson, L. N. (2011) The American journal of pathology 178, 2286-2298. PubMed
  • Thermodynamic stability and denaturation kinetics of a benign natural transthyretin mutant identified in a Danish kindred, Groenning, M., Campos, R. I., Fagerberg, C., Rasmussen, A. A., Eriksen, U. H., Powers, E. T., and Hammarstrom, P. (2011) Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 18, 35-46. PubMed
  • Spectroscopic characterization of diverse amyloid fibrils in vitro by the fluorescent dye Nile red, Mishra, R., Sjolander, D., and Hammarstrom, P. (2011) Molecular bioSystems 7, 1232-1240. PubMed
  • An auto-catalytic surface for conformational replication of amyloid fibrils--genesis of an amyloid world? Hammarstrom, P., Ali, M. M., Mishra, R., Salagic, B., Svensson, S., Tengvall, P., and Lundstrom, I. (2011) Origins of life and evolution of the biosphere : the journal of the International Society for the Study of the Origin of Life 41, 373-383. PubMed
  • Spatially controlled amyloid reactions using organic electronics, Gabrielsson, E. O., Tybrandt, K., Hammarstrom, P., Berggren, M., and Nilsson, K. P. (2010) Small 6, 2153-2161. PubMed
  • A fluorescent pentameric thiophene derivative detects in vitro-formed prefibrillar protein aggregates, Hammarstrom, P., Simon, R., Nystrom, S., Konradsson, P., Aslund, A., and Nilsson, K. P. (2010) Biochemistry 49, 6838-6845. PubMed
  • Efficient imaging of amyloid deposits in Drosophila models of human amyloidoses, Berg, I., Nilsson, K. P., Thor, S., and Hammarstrom, P. (2010) Nature protocols 5, 935-944. PubMed
  • Amyloid oligomers: spectroscopic characterization of amyloidogenic protein states, Lindgren, M., and Hammarstrom, P. (2010) The FEBS journal 277, 1380-1388. PubMed
  • Chaperone activity of Cyp18 through hydrophobic condensation that enables rescue of transient misfolded molten globule intermediates, Moparthi, S. B., Fristedt, R., Mishra, R., Almstedt, K., Karlsson, M., Hammarstrom, P., and Carlsson, U. (2010) Biochemistry 49, 1137-1145. PubMed
  • GroEL-induced topological dislocation of a substrate protein beta-sheet core: a solution EPR spin-spin distance study, Owenius, R., Jarl, A., Jonsson, B. H., Carlsson, U., and Hammarstrom, P. (2010) Journal of chemical biology 3, 127-139. Pubmed
  • Luminescence and two-photon absorption cross section of novel oligomeric luminescent conjugated polythiophenes for diagnostics of amyloid fibrils Lindgren, M. Glimsdal, E. Åslund, A. Simon, R., Hammarström, P., Nilsson, P. (2010) Nonlinear Optics Quantum Optics 40, 241-251
  • Amyloid fibrils of human prion protein are spun and woven from morphologically disordered aggregates, Almstedt, K., Nystrom, S., Nilsson, K. P., and Hammarstrom, P. (2009) Prion 3, 224-235. Pubmed 
  • Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses, Aslund, A., Sigurdson, C. J., Klingstedt, T., Grathwohl, S., Bolmont, T., Dickstein, D. L., Glimsdal, E., Prokop, S., Lindgren, M., Konradsson, P., Holtzman, D. M., Hof, P. R., Heppner, F. L., Gandy, S., Jucker, M., Aguzzi, A., Hammarstrom, P., and Nilsson, K. P. (2009) ACS chemical biology 4, 673-684. Pubmed
  • Protein folding, misfolding and disease, Hammarstrom, P. (2009) FEBS letters 583, 2579-2580. PubMed
  • Small-molecule suppression of misfolding of mutated human carbonic anhydrase II linked to marble brain disease, Almstedt, K., Rafstedt, T., Supuran, C. T., Carlsson, U., and Hammarstrom, P. (2009) Biochemistry 48, 5358-5364. PubMed
  • Modeling familial amyloidotic polyneuropathy (Transthyretin V30M) in Drosophila melanogaster, Berg, I., Thor, S., and Hammarstrom, P. (2009) Neuro-degenerative diseases 6, 127-138. PubMed
  • A nonessential role for Arg 55 in cyclophilin18 for catalysis of proline isomerization during protein folding, Moparthi, S. B., Hammarstrom, P., and Carlsson, U. (2009) Protein science : a publication of the Protein Society 18, 475-479. PubMed
  • A highly insoluble state of Abeta similar to that of Alzheimer's disease brain is found in Arctic APP transgenic mice, Philipson, O., Hammarstrom, P., Nilsson, K. P., Portelius, E., Olofsson, T., Ingelsson, M., Hyman, B. T., Blennow, K., Lannfelt, L., Kalimo, H., and Nilsson, L. N. (2009) Neurobiology of aging 30, 1393-1405. PubMed
  • Prefibrillar transthyretin oligomers and cold stored native tetrameric transthyretin are cytotoxic in cell culture, Sorgjerd, K., Klingstedt, T., Lindgren, M., Kagedal, K., and Hammarstrom, P. (2008) Biochemical and biophysical research communications 377, 1072-1078. PubMed
  • Misfolded proteins activate factor XII in humans, leading to kallikrein formation without initiating coagulation, Maas, C., Govers-Riemslag, J. W., Bouma, B., Schiks, B., Hazenberg, B. P., Lokhorst, H. M., Hammarstrom, P., ten Cate, H., de Groot, P. G., Bouma, B. N., and Gebbink, M. F. (2008) The Journal of clinical investigation 118, 3208-3218. Pubmed
  • Native, amyloid fibrils and beta-oligomers of the C-terminal domain of human prion protein display differential activation of complement and bind C1q, factor H and C4b-binding protein directly, Sjoberg, A. P., Nystrom, S., Hammarstrom, P., and Blom, A. M. (2008) Molecular immunology 45, 3213-3221. PubMed
  • A conformationally isoformic thermophilic protein with high kinetic unfolding barriers, Mishra, R., Olofsson, L., Karlsson, M., Carlsson, U., Nicholls, I. A., and Hammarstrom, P. (2008) Cellular and molecular life sciences : CMLS 65, 827-839. PubMed
  • Luminescent conjugated polymers: Illuminating the Dark Matters of Biology and Pathology Nilsson, K. P. R., and Hammarström, P.  (2008) Advanced  Materials 20:2639-2645 Wiley online library
  • Thermodynamic interrogation of a folding disease. Mutant mapping of position 107 in human carbonic anhydrase II linked to marble brain disease, Almstedt, K., Martensson, L. G., Carlsson, U., and Hammarstrom, P. (2008) Biochemistry 47, 1288-1298. PubMed
  • Prion strain discrimination using luminescent conjugated polymers, Sigurdson, C. J., Nilsson, K. P., Hornemann, S., Manco, G., Polymenidou, M., Schwarz, P., Leclerc, M., Hammarstrom, P., Wuthrich, K., and Aguzzi, A. (2007) Nature methods 4, 1023-1030. PubMed
  • Studies of luminescent conjugated polythiophene derivatives: enhanced spectral discrimination of protein conformational states, Aslund, A., Herland, A., Hammarstrom, P., Nilsson, K. P., Jonsson, B. H., Inganas, O., and Konradsson, P. (2007) Bioconjugate chemistry 18, 1860-1868. PubMed
  • Domain-specific chaperone-induced expansion is required for beta-actin folding: a comparison of beta-actin conformations upon interactions with GroEL and tail-less complex polypeptide 1 ring complex (TRiC), Villebeck, L., Moparthi, S. B., Lindgren, M., Hammarstrom, P., and Jonsson, B. H. (2007) Biochemistry 46, 12639-12647. PubMed
  • Imaging distinct conformational states of amyloid-beta fibrils in Alzheimer's disease using novel luminescent probes, Nilsson, K. P., Aslund, A., Berg, I., Nystrom, S., Konradsson, P., Herland, A., Inganas, O., Stabo-Eeg, F., Lindgren, M., Westermark, G. T., Lannfelt, L., Nilsson, L. N., and Hammarstrom, P. (2007) ACS chemical biology 2, 553-560. PubMed
  • The bloody path of amyloids and prions, Hammarstrom, P. (2007) Journal of thrombosis and haemostasis : JTH 5, 1136-1138. PubMed
  • Conformational rearrangements of tail-less complex polypeptide 1 (TCP-1) ring complex (TRiC)-bound actin, Villebeck, L., Persson, M., Luan, S. L., Hammarstrom, P., Lindgren, M., and Jonsson, B. H. (2007) Biochemistry 46, 5083-5093. PubMed
  • Lysozyme amyloidogenesis is accelerated by specific nicking and fragmentation but decelerated by intact protein binding and conversion, Mishra, R., Sorgjerd, K., Nystrom, S., Nordigarden, A., Yu, Y. C., and Hammarstrom, P. (2007) Journal of molecular biology 366, 1029-1044. PubMed
  • Conjugated polyelectrolytes--conformation-sensitive optical probes for staining and characterization of amyloid deposits, Nilsson, K. P., Hammarstrom, P., Ahlgren, F., Herland, A., Schnell, E. A., Lindgren, M., Westermark, G. T., and Inganas, O. (2006) Chembiochem 7, 1096-1104. PubMed
  • Retention of misfolded mutant transthyretin by the chaperone BiP/GRP78 mitigates amyloidogenesis, Sorgjerd, K., Ghafouri, B., Jonsson, B. H., Kelly, J. W., Blond, S. Y., and Hammarstrom, P. (2006) Journal of molecular biology 356, 469-482. PubMed
  • The cyclooxygenase-2 inhibitor celecoxib is a potent inhibitor of human carbonic anhydrase II, Knudsen, J. F., Carlsson, U., Hammarstrom, P., Sokol, G. H., and Cantilena, L. R. (2004) Inflammation 28, 285-290. PubMed
  • Activity, folding, misfolding, and aggregation in vitro of the naturally occurring human tissue factor mutant R200W, Wirehn, J., Carlsson, K., Herland, A., Persson, E., Carlsson, U., Svensson, M., and Hammarstrom, P. (2005) Biochemistry 44, 6755-6763. PubMed
  • The biological and chemical basis for tissue-selective amyloid disease, Sekijima, Y., Wiseman, R. L., Matteson, J., Hammarstrom, P., Miller, S. R., Sawkar, A. R., Balch, W. E., and Kelly, J. W. (2005) Cell 121, 73-85. PubMed
  • Detection and characterization of aggregates, prefibrillar amyloidogenic oligomers, and protofibrils using fluorescence spectroscopy, Lindgren, M., Sorgjerd, K., and Hammarstrom, P. (2005) Biophysical journal 88, 4200-4212. PubMed
  • Conjugated polyelectrolytes: conformation-sensitive optical probes for detection of amyloid fibril formation, Nilsson, K. P., Herland, A., Hammarstrom, P., and Inganas, O. (2005) Biochemistry 44, 3718-3724. PubMed
  • Synthesis of a regioregular zwitterionic conjugated oligoelectrolyte, usable as an optical probe for detection of amyloid fibril formation at acidic pH, Herland, A., Nilsson, K. P., Olsson, J. D., Hammarstrom, P., Konradsson, P., and Inganas, O. (2005) Journal of the American Chemical Society 127, 2317-2323. PubMed
  • Unfolding a folding disease: folding, misfolding and aggregation of the marble brain syndrome-associated mutant H107Y of human carbonic anhydrase II, Almstedt, K., Lundqvist, M., Carlsson, J., Karlsson, M., Persson, B., Jonsson, B. H., Carlsson, U., and Hammarstrom, P. (2004) Journal of molecular biology 342, 619-633. PubMed
  • Reshaping the folding energy landscape by chloride salt: impact on molten-globule formation and aggregation behavior of carbonic anhydrase, Boren, K., Grankvist, H., Hammarstrom, P., and Carlsson, U. (2004) FEBS letters 566, 95-99. PubMed
  • D18G transthyretin is monomeric, aggregation prone, and not detectable in plasma and cerebrospinal fluid: a prescription for central nervous system amyloidosis? Hammarstrom, P., Sekijima, Y., White, J. T., Wiseman, R. L., Lim, A., Costello, C. E., Altland, K., Garzuly, F., Budka, H., and Kelly, J. W. (2003) Biochemistry 42, 6656-6663. PubMed
  • Energetic characteristics of the new transthyretin variant A25T may explain its atypical central nervous system pathology, Sekijima, Y., Hammarstrom, P., Matsumura, M., Shimizu, Y., Iwata, M., Tokuda, T., Ikeda, S., and Kelly, J. W. (2003) Laboratory investigation; a journal of technical methods and pathology 83, 409-417. PubMed
  • Prevention of transthyretin amyloid disease by changing protein misfolding energetics, Hammarstrom, P., Wiseman, R. L., Powers, E. T., and Kelly, J. W. (2003) Science (New York, N.Y 299, 713-716). PubMed
  • Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity, Hammarstrom, P., Jiang, X., Hurshman, A. R., Powers, E. T., and Kelly, J. W. (2002) Proceedings of the National Academy of Sciences of the United States of America 99 Suppl 4, 16427-16432. Pubmed
  • Phase memory relaxation times of spin labels in human carbonic anhydrase II: pulsed EPR to determine spin label location, Huber, M., Lindgren, M., Hammarstrom, P., Martensson, L. G., Carlsson, U., Eaton, G. R., and Eaton, S. S. (2001) Biophysical chemistry 94, 245-256. PubMed
  • Trans-suppression of misfolding in an amyloid disease, Hammarstrom, P., Schneider, F., and Kelly, J. W. (2001) Science (New York, N.Y 293, 2459-2462. PubMed
  • Anion shielding of electrostatic repulsions in transthyretin modulates stability and amyloidosis: insight into the chaotrope unfolding dichotomy, Hammarstrom, P., Jiang, X., Deechongkit, S., and Kelly, J. W. (2001) Biochemistry 40, 11453-11459. PubMed
  • An engineered transthyretin monomer that is nonamyloidogenic, unless it is partially denatured, Jiang, X., Smith, C. S., Petrassi, H. M., Hammarstrom, P., White, J. T., Sacchettini, J. C., and Kelly, J. W. (2001) Biochemistry 40, 11442-11452.  PubMed
  • Transthyretin slowly exchanges subunits under physiological conditions: A convenient chromatographic method to study subunit exchange in oligomeric proteins, Schneider, F., Hammarstrom, P., and Kelly, J. W. (2001) Protein science : a publication of the Protein Society 10, 1606-1613. Pubmed
  • Comparison of electron paramagnetic resonance methods to determine distances between spin labels on human carbonic anhydrase II, Persson, M., Harbridge, J. R., Hammarstrom, P., Mitri, R., Martensson, L. G., Carlsson, U., Eaton, G. R., and Eaton, S. S. (2001) Biophysical journal 80, 2886-2897. Pubmed
  • High-resolution probing of local conformational changes in proteins by the use of multiple labeling: unfolding and self-assembly of human carbonic anhydrase II monitored by spin, fluorescent, and chemical reactivity probes, Hammarstrom, P., Owenius, R., Martensson, L. G., Carlsson, U., and Lindgren, M. (2001) Biophysical journal 80, 2867-2885. Pubmed
  • Protein compactness measured by fluorescence resonance energy transfer. Human carbonic anhydrase ii is considerably expanded by the interaction of GroEL, Hammarstrom, P., Persson, M., and Carlsson, U. (2001) The Journal of biological chemistry 276, 21765-21775. Pubmed
  • Cofactor-induced refolding: refolding of molten globule carbonic anhydrase induced by Zn(II) and Co(II), Andersson, D., Hammarstrom, P., and Carlsson, U. (2001) Biochemistry 40, 2653-2661. PubMed
  • Is the unfolded state the Rosetta Stone of the protein folding problem?, Hammarstrom, P., and Carlsson, U. (2000) Biochemical and biophysical research communications 276, 393-398. PubMed
  • Protein substrate binding induces conformational changes in the chaperonin GroEL. A suggested mechanism for unfoldase activity, Hammarstrom, P., Persson, M., Owenius, R., Lindgren, M., and Carlsson, U. (2000) The Journal of biological chemistry 275, 22832-22838. Pubmed
  • Structural mapping of an aggregation nucleation site in a molten globule intermediate, Hammarstrom, P., Persson, M., Freskgard, P. O., Martensson, L. G., Andersson, D., Jonsson, B. H., and Carlsson, U. (1999) The Journal of biological chemistry 274, 32897-32903. Pubmed
  • EPR mapping of interactions between spin-labeled variants of human carbonic anhydrase II and GroEL: evidence for increased flexibility of the hydrophobic core by the interaction, Persson, M., Hammarstrom, P., Lindgren, M., Jonsson, B. H., Svensson, M., and Carlsson, U. (1999) Biochemistry 38, 432-441. PubMed
  • Pyrene excimer fluorescence as a proximity probe for investigation of residual structure in the unfolded state of human carbonic anhydrase II, Hammarstrom, P., Kalman, B., Jonsson, B. H., and Carlsson, U. (1997) FEBS letters 420, 63-68. PubMed