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

ArticleinBrain Pathology 16(1):55-9 · February 2006with17 Reads
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.
    • "The other protein, hCC, and, in particular, the naturally occurring hCC mutant L68Q, also show a tendency toward dimerization, oligomerization, and amyloid fibril formation. This propensity is dramatically manifested in hereditary cystatin C amyloid angiopathy (HCCAA), which occurs as a result of hCC gene mutation (Palsdottir et al., 1989Palsdottir et al., , 2006 ). Cystatin C aggregation during HCCAA affects relatively young people and leads to M. SPODZIEJA ET AL. "
    [Show abstract] [Hide abstract] 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
    • "Basically, all forms of CAA non-related to Aβ are hereditary and accompanied by an increased risk of ICB and dementia (Revesz et al., 2009). In the case of the autosomal dominating Island-type CAA, as a consequence of a mutation of the cystatin C gene, a modified cystatin C protein is stored, which can mainly be encountered in the cerebral arteries, and occasionally in other arteries of the body as well (Palsdottier et al., 2006; Revesz et al., 2009). Patients suffering from this form of CAA become ill with lobar located ICB and dementia, in most cases between their twentieth and their thirtieth year. "
    [Show abstract] [Hide abstract] ABSTRACT: Cerebral Amyloidal Angiopathy (CAA), which occurs sporadically in most cases but can also occur hereditary, belongs to the group amyloidoses and is characterized by the deposition and accumulation of beta-Amyloidal (Aβ) in smaller arterial vessels of the brain. The deposit of Aβ leads to degenerative changes in the cerebral vessel system (thickening of the vessel wall, microaneurysm, constriction of vascular lumen, dissection), which favour the development of the clinical symptomatology most often associated with CAA. Besides haemorrhages, cerebral ischemia, transient neurological symptoms, leukoencephalopathy as well as cognitive decline and even dementia may appear in connection with CAA. A definite diagnosis of CAA can only be made on the basis of a pathological assessment, even though diagnostic findings of cerebral neuroimaging and clinical symptoms allow the diagnosis of a probable CAA. At present, no causal therapy options are available. Although CAA is placed within the range of neurological illnesses, psychiatric symptoms such as cognitive impairment, personality change or behavioural problems as well as depression are plausible clinical manifestations of CAA and may even dominate the clinical picture. Apart from epidemiological, pathogenetical, clinical and diagnostical aspects, possible psychiatric implications of CAA are discussed in the review article.
    Article · May 2013
    • "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). "
    [Show abstract] [Hide abstract] 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
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