Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the amyloid beta protein (Abeta) E693Q mutation enhances Abeta fibrillization in vitro and cerebral amyloid angiopathy (CAA) in vivo, brain parenchymal Abeta deposition and tau pathology in hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) are limited. To evaluate whether clearance of Abeta by glial cells may play a role in this regard, this immunohistochemical study of frontal cortex of 14 HCHWA-D autopsy brains was performed using double staining with glial markers and end-specific antibodies to Abetax-42 (Abeta42) and Abetax-40 (Abeta40). Tau pathology was also assessed. Numerous microglia and/or astrocytes carrying cytoplasmic Abeta42(+)40(-) granules were scattered among non-fibrillar (Congo red-negative) Abeta deposits, i.e., clouds, fine diffuse plaques, and Abeta42(+)40(-) dense diffuse plaques. On the other hand, activated microglia and reactive astrocytes associated with fibrillar (Congo red-positive) Abeta deposition, i.e., Abeta42(+)40(+) dense diffuse plaques and CAA invading the parenchyma, were virtually devoid of Abeta granules. Tau pathology was scant and most frequently associated with CAA. These results suggest that relatively non-fibrillar parenchymal Abeta deposits may be liable to glial clearance. Abeta sequestration by glial cells may be a factor limiting the levels of neurotoxic soluble Abeta oligomers in HCHWA-D brain.
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PMID:Glial reactions and the clearance of amyloid beta protein in the brains of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type. 1501 55

CRES (cystatin-related epididymal spermatogenic), a member of the cystatin superfamily of cysteine protease inhibitors, is expressed in the epididymis and spermatozoa, suggesting specialized roles in reproduction. Several cystatin family members oligomerize, including cystatin C that forms amyloid deposits associated with cerebral amyloid angiopathy. Our studies demonstrate that CRES also forms oligomers. Size exclusion chromatography revealed the presence of multiple forms of CRES in the epididymal luminal fluid, including SDS-sensitive and SDS-resistant high molecular mass complexes. In vitro experiments demonstrated that CRES is a substrate for transglutaminase and that an endogenous transglutaminase activity in the epididymal lumen catalyzed the formation of SDS-resistant CRES complexes. The use of a conformation-dependent antibody that recognizes only the oligomeric precursors to amyloid, negative stain electron microscopy, and Congo Red staining showed that CRES adopted similar oligomeric and fibrillar structures during its aggregation as other amyloidogenic proteins, suggesting that CRES has the potential to form amyloid in the epididymal lumen. The addition of transglutaminase, however, prevented the formation of CRES oligomers recognized by the conformation antibody by cross-linking CRES into an amorphous structure. We propose that transglutaminase activity in the epididymal lumen may function as a mechanism of extracellular quality control by diverting proteins such as CRES from the amyloidogenic pathway.
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PMID:Oligomerization and transglutaminase cross-linking of the cystatin CRES in the mouse epididymal lumen: potential mechanism of extracellular quality control. 1785 42

Amyloid is a term used to describe protein deposits with circumscript physical characteristics: beta-pleated sheet configuration, apple green birefringence under polarized light after Congo red staining, fibrillary structure and high insolubility. Cerebral amyloid angiopathy (CAA) defines a clinicopathological phenomenon characterized by amyloid deposition in the walls of leptomeningeal and cortical arteries, arterioles, and, less often capillaries and veins of the central nervous system. CAAs are currently classified according to the protein deposited including amyloid beta peptide (Abeta), cystatin C (ACys C), prion protein (PrP(Sc)), ABri/ADan, transthyretin (ATTR), and gelsolin (AGel). Most often amyloid deposition occurs in sporadic forms. In less common hereditary forms, a mutated variant protein or precursor protein is abnormally metabolized by proteolytic pathways in consequence of specific gene mutations, and accumulates as amyloid. The spectrum of clinical phenotypes associated with CAA-related vasculopathic changes includes both ischemic and hemorrhagic presentations, primary intracerebral hemorrhage (PICH) being probably the most well-recognized. However, in spite of accumulating data and recent progress in understanding the pathogenesis of CAA-related hemorrhage, the exact mechanisms leading to vessel rupture in these cases are yet to be established. This represents, at present, a major limitation to the identification of reliable biomarkers and the development of disease-specific treatment options. The present paper summarizes epidemiologic and clinical aspects of CAA, and highlights the presumed pathomechanisms of amyloid deposition in both sporadic and hereditary forms.
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PMID:Cerebral amyloid angiopathy: a common cause of cerebral hemorrhage. 1960 95

Human cystatin C (HCC) is a low molecular weight member of the cystatin family (type2). HCC consists of 120 amino acids. Normally it is an inhibitor of cysteine proteases, but in pathological conditions it forms amyloid fibrils in brain arteries of young adults. An 'aggregation-prone' pentapeptide ((47)LQVVR(51)) was located within the HCC sequence using AmylPred, an 'aggregation-prone' peptide prediction algorithm developed in our lab. This peptide was synthesized and self-assembled into amyloid-like fibrils in vitro, as electron microscopy, X-ray fiber diffraction, Attenuated Total Reflectance Fourier-Transform Spectroscopy and Congo red staining studies reveal. Thus, the (47)LQVVR(51) peptide seems to have an important role in HCC fibrillization.
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PMID:The pentapeptide LQVVR plays a pivotal role in human cystatin C fibrillization. 2547 90


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