Hereditary Cystatin C Amyloid Angiopathy: Genetic, Clinical, and Pathological Aspects

Institute for Experimental Pathology, Reykjavik, University of Iceland.
Brain Pathology (Impact Factor: 3.84). 02/2006; 16(1):55-9. DOI: 10.1111/j.1750-3639.2006.tb00561.x
Source: PubMed


Hereditary cystatin C amyloid angiopathy (HCCAA) is a rare, fatal amyloid disease in young people in Iceland caused by a mutation in cystatin C, which is an inhibitor of several cysteine proteinases, such as cathepsins S, B, and K. The same mutation in cystatin C, l68Q, has been found in all patients examined so far pointing to a common founder. Most of the families can be traced to a region in the northwest of Iceland, around Breidafjordur bay. Mutated cystatin c forms amyloid, predominantly in brain arteries and arterioles, but also to a lesser degree in tissues outside the central nervous system such as skin, lymph nodes, testis, spleen, submandibular salivary glands, and adrenal cortex. The amyloid deposition in the vessel walls causes thickening of the walls leading to occlusion or rupture and resulting in brain hemorrhage.
Although the amyloid can be detected outside the brain, the clinical manifestation is restricted to the brain, and usually consists of repeated hemorrhages leading to paralysis. sometimes the initial signs of hemorrhage are dementia and personality changes.

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    • "Furthermore , hCC is used as a popular biomarker for kidney function (Reed, 2000; Grubb, 2010; Grubb et al., 2011). The protein, and especially its variant L68Q hCC, reveals amyloidogenic properties and has been found as a component in the amyloid deposits of patients with hereditary cystatin C amyloid angiopathy (HCCAA) (Palsdottir et al., 2006). On the other hand, there is also clinical and experimental evidence supporting a protective quality of hCC against cerebral amyloidosis (Sastre et al., 2004; Mi et al., 2007; Levy, 2008). "
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    ABSTRACT: Secondary amyloid A (AA) amyloidosis is an important complication of some chronic inflammatory diseases, primarily rheumatoid arthritis (RA). It is a serious, potentially life-threatening disorder caused by the deposition of AA fibrils, which are derived from the circulatory, acute-phase-reactant, serum amyloid A protein (SAA). Recently, a specific interaction between SAA and the ubiquitous inhibitor of cysteine proteases-human cystatin C (hCC)-has been proved. Using a combination of selective proteolytic excision and high-resolution mass spectrometry, the binding sites in the SAA and hCC sequences were assessed as SAA(86-104) and hCC(96-102), respectively. Here, we report further details concerning the hCC-SAA interaction. With the use of affinity tests and florescent ELISA-like assays, the amino acid residues crucial for the protein interaction were determined. It was shown that all amino acid residues in the SAA sequence, essential for the formation of the protein complex, are basic ones, which suggests an electrostatic interaction character. The idea is corroborated by the fact that the most important residues in the hCC sequence are Ser-98 and Tyr-102; these residues are able to form hydrogen bonds via their hydroxyl groups. The molecular details of hCC-SAA complex formation might be helpful for the design of new compounds modulating the biological role of both proteins. Copyright © 2013 John Wiley & Sons, Ltd.
    Full-text · Article · Sep 2013 · Journal of Molecular Recognition
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    • "Soluble hCC L68Q oligomers can be detected in body fluids, but aggregation of this protein primarily affects the brain (Olafsson et al., 1996). Accumulation of hCC L68Q deposits in brain arteries leads to development of an amyloidogenic disease— HCCAA, which is manifested by numerous hemorrhages, strokes, and finally death, often before 40 years of age (Palsdottir et al., 2006). "
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    ABSTRACT: Human cystatin C (hCC) is a small but very intriguing protein. Produced by all nucleated cells is found in almost all tissues and body fluids where, at physiological conditions, plays a role of a very potent inhibitor of cysteine proteases. Biologically active hCC is a monomeric protein but during cellular trafficking it forms dimers, transiently losing its inhibitory activity. In vitro, dimerization of cystatin C was observed for the mature protein during crystallization trials, revealing that the mechanism of this process is based on the three dimensional swapping of the protein domains. In our work we have focused on the impact of two proposed "hot spots" in cystatin C structure on its conformational stability. Encouraged by promising results of the theoretical calculations, we designed and produced several hCC hinge region point mutation variants that display a variety of conformational stability and propensity for dimerization and aggregation. A similar approach, i.e., rational mutagenesis, has been also applied to study the amyloidogenic L68Q variant to determine the contribution of hydrophobic interactions and steric effect on the stability of monomeric cystatin C. In this overview we would like to summarize the results of our studies. The impact of a particular mutation on the properties of the studied proteins will be presented in the context of their thermal and mechanical stability, in vitro dimerization tendency as well as the outcome of crystallization. Better understanding of the mechanism and, especially, factors affecting conformational stability of cystatin C and access to stable monomeric and dimeric versions of the protein opens new perspectives in explaining the role of dimers and the domain swapping process in hCC oligomerization, as well as designing potential inhibitors of this process.
    Full-text · Article · Jul 2012 · Frontiers in Molecular Neuroscience
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    • "In vitro studies of the recombinant CRES protein demonstrated that it has the capacity to readily form oligomeric and fibrillar amyloid-like structures characteristic of those present in pathological conditions such as Alzheimer's disease [6]. In this regard CRES is similar to the L68Q mutant form of human cystatin C which readily forms amyloid and is the causative factor of hereditary cystatin C amyloid angiopathy (HCCAA) in the Icelandic population [8]. Our observation that CRES forms amyloid in vitro raised the question of whether CRES might also form amyloid in vivo and thus explain the transition of monomer to high molecular mass structures. "
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    ABSTRACT: Amyloids are aggregated proteins characterized by a specific cross-β-sheet structure and are typically associated with neurodegenerative diseases including Alzheimer's disease. Recently, however, several nonpathological amyloids have been found in intracellular organelles of normal mammalian tissues suggesting that amyloid may also carry out biological functions. We previously have shown that the epididymal cystatin CRES (cystatin-related epididymal spermatogenic), cst8, a reproductive-specific member of the cystatin superfamily of cysteine protease inhibitors, forms amyloid in vitro suggesting that CRES amyloid may also form in vivo within the epididymal lumen. Here we show that amyloid structures containing CRES are a component of the normal mouse epididymal lumen without any apparent cytotoxic effects on spermatozoa and that these structures change along the length of the tubule. These studies suggest the presence of a functional amyloid structure that may carry out roles in sperm maturation or maintenance of the luminal milieu and which itself may undergo maturational changes along the epididymis. In contrast to previous examples of functional amyloid which were intracellular, our studies now show that nonpathological/functional amyloid can also be extracellular. The presence of an extracellular and nonpathological amyloid in the epididymis suggests that similar amyloid structures may be present in other organ systems and may carry out distinctive tissue-specific functions.
    Full-text · Article · May 2012 · PLoS ONE
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