The cerebral hemorrhage-producing cystatin C variant (L68Q) in extracellular fluids

Bjarnadóttir, María; Nilsson, Carol L.; Lindström, Veronica; Westman, Ann; Davidsson, Pia; Thormodsson, Finnbogi R.; Blöndal, Hannes; Guðmundsson, Gunnar; Grubb, Anders

doi:10.3109/13506120108993809

Cited by 43 publications

(34 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The cystatin C dimer is the only molecular form of cystatin C that has been detected in body fluids besides monomeric cystatin C and amyloid fibrils (8). Although dimeric cystatin C could be an intermediate in the transformation of monomeric cystatin C to amyloid fibrils, an alternative hypothesis is that the dimers are potential dead-end products on the oligomerization pathway (10,22).…”

Section: Discussionmentioning

confidence: 99%

“…Patients suffering from Hereditary Cystatin C Amyloid Angiopathy (HCCAA) have L68Q cystatin C deposited as amyloid fibrils in the cerebral arteries, resulting in cerebral hemorrhage and death in early adulthood (7). In the blood plasma and cerebrospinal fluid of HCCAA patients, high concentrations of non-physiological cystatin C dimers are detected (8). Moreover, wt cystatin C participates in the formation of amyloid deposits together with the A␤ peptide (1,2).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Fibrillogenic Oligomers of Human Cystatin C Are Formed by Propagated Domain Swapping

Wahlbom

Wang

Lindström

et al. 2007

Journal of Biological Chemistry

Self Cite

118

132

View full text Add to dashboard Cite

Cystatin C and the prion protein have been shown to form dimers via three-dimensional domain swapping, and this process has also been hypothesized to be involved in amyloidogenesis. Production of oligomers of other amyloidogenic proteins has been reported to precede fibril formation, suggesting oligomers as intermediates in fibrillogenesis. A variant of cystatin C, with a Leu 68 3 Gln substitution, is highly amyloidogenic, and carriers of this mutation suffer from massive cerebral amyloidosis leading to brain hemorrhage and death in early adulthood. This work describes doughnut-shaped oligomers formed by wild type and L68Q cystatin C upon incubation of the monomeric proteins. Purified oligomers of cystatin C are shown to fibrillize faster and at a lower concentration than the monomeric protein, indicating a role of the oligomers as fibril-assembly intermediates. Moreover, the present work demonstrates that three-dimensional domain swapping is involved in the formation of the oligomers, because variants of monomeric cystatin C, stabilized against three-dimensional domain swapping by engineered disulfide bonds, do not produce oligomers upon incubation under non-reducing conditions. Redox experiments using wild type and stabilized cystatin C strongly suggest that the oligomers, and thus probably the fibrils as well, are formed by propagated domain swapping rather than by assembly of domain-swapped cystatin C dimers.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Fibrillogenic Oligomers of Human Cystatin C Are Formed by Propagated Domain Swapping

Wahlbom

Wang

Lindström

et al. 2007

Journal of Biological Chemistry

Self Cite

118

132

View full text Add to dashboard Cite

show abstract

“…Experimental investigation indicated that dimers can be formed more easily between unfolded cC As mentioned above, an unintelligible phenomenon between cC and hCC is that WT cC is thermodynamically stable and its monomers can present in physiological condition but hCC cannot (Bjarnadottir et al, 2001;Sanders et al, 2004). Even though Szymańska et al (2009) had speculated that the turn-formation propensity of WT hCC might contribute to their ability to form domain-swapped dimers, why cC is not easy to dimerize is still unknown.…”

Section: An Independent Investigation Predicted That Switch Region Ofmentioning

confidence: 99%

“…However, one obvious difference between cC and hCC is that WT cC is thermodynamically stable and its monomers can present in physiological condition, while WT hCC is extremely unstable and easily become dimers which lead to forming amyloid deposits (Bjarnadottir et al, 2001). Thus, cC is more convenient than hCC in the simulated and experimental studies of cystatin dimerization.…”

Section: Introductionmentioning

confidence: 99%

Appendant structure plays an important role in amyloidogenic cystatin dimerization prior to domain swapping

Liu

et al. 2012

Journal of Biomolecular Structure and Dynamics

View full text Add to dashboard Cite

“…It has been suggested that the cystatin C amyloid fibrils are generated by propagated domain swapping between cystatin C monomers in which N-and Cterminal parts of the monomers are exchanged, forming long protein chains [5,6]. Whereas L68Q-cystatin C easily forms dimers and amyloid fibrils in vivo and in vitro [7,8], wildtype cystatin C requires mild denaturing conditions to form dimers and amyloid fibrils in vitro [6,9]. Importantly, if variants of wildtype cystatin C and L68Q-cystatin C with intra-chain stabilizing disulfide bonds preventing domain swapping are produced, these variants cannot be induced to form neither dimers nor amyloid fibrils [6,9].…”

Section: Introductionmentioning

confidence: 99%

High throughput testing of drug library substances and monoclonal antibodies for capacity to reduce formation of cystatin C dimers to identify candidates for treatment of hereditary cystatin C amyloid angiopathy

Östner¹,

Lindström²,

Postnikov³

et al. 2011

Scandinavian Journal of Clinical and Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

High throughput testing of drug library substances and monoclonal antibodies for capacity to reduce formation of cystatin C dimers to identify candidates for treatment of hereditary cystatin C amyloid angiopathy.Östner, Gustav; Lindström, Veronica; Postnikov, Alexander B; Solovyeva, Tatiana I; Emilsson, Ossur I; Grubb, Anders Östner, G., Lindström, V., Postnikov, A. B., Solovyeva, T. I., Emilsson, O. I., & Grubb, A. (2011). High throughput testing of drug library substances and monoclonal antibodies for capacity to reduce formation of cystatin C dimers to identify candidates for treatment of hereditary cystatin C amyloid angiopathy. Scandinavian Journal of Clinical and Laboratory Investigation, 71(8), 676-682. https://doi.org/10.3109/00365513.2011.621026 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. AbstractObjective. To establish a high-throughput system for testing the ability of drugs or monoclonal antibodies to reduce the in vitro formation of cystatin C dimers to identify substances potentially useful for treatment of patients with hereditary cystatin C amyloid angiopathy (HCCAA). Methods. Various combinations of incubation temperature, time period, guanidinium chloride concentration and concentration of cystatin C monomers were tested in low-volume formats to induce dimer formation of recombinant cystatin C. The extent of dimerization was analysed by gel filtration chromatography and agarose gel electrophoresis. Results. A high-throughput system based upon agarose gel electrophoresis was developed and used to test 1040 drugs in a clinical drug library for their capacity to reduce cystatin C dimer formation in vitro. Seventeen substances reducing dimer formation by more than 30% were identified. A similar system for testing the capacity of monoclonal antibodies against cystatin C to reduce the in vitro formation of cystatin C dimers was also developed and used to test a panel of 12 monoclonal antibodies. Seven antibodies reducing dimer formation by more than 30% were identified and the two most potent, Cyst28 and HCC3, reduced dimerization by 75 and 60%, respectively. Conclusion. We constructed a simple high-throughput system for testing the capacity of drugs and monoclonal antibodies to reduce the in vitro formation of cystatin C dimers and several candidates for trea...

show abstract

The cerebral hemorrhage-producing cystatin C variant (L68Q) in extracellular fluids

Cited by 43 publications

References 47 publications

Fibrillogenic Oligomers of Human Cystatin C Are Formed by Propagated Domain Swapping

Fibrillogenic Oligomers of Human Cystatin C Are Formed by Propagated Domain Swapping

Appendant structure plays an important role in amyloidogenic cystatin dimerization prior to domain swapping

High throughput testing of drug library substances and monoclonal antibodies for capacity to reduce formation of cystatin C dimers to identify candidates for treatment of hereditary cystatin C amyloid angiopathy

Contact Info

Product

Resources

About