NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadHereditary cystatin C amyloid angiopathy is a dominantly inherited disease caused by a leucine to glutamine variant of human cystatin C (hCC). L68Q-hCC forms amyloid deposits in brain arteries associated with micro-infarcts, leading ultimately to paralysis, dementia and death in young adults. To evaluate the ability of molecules to interfere with aggregation of hCC while informing about cellular toxicity, we generated cells that produce and secrete WT and L68Q-hCC and have detected high-molecular weight complexes formed from the mutant protein. Incubations of either lysate or supernatant containing L68Q-hCC with reducing agents glutathione or N-acetyl-cysteine (NAC) breaks oligomers into monomers. Six L68Q-hCC carriers taking NAC had skin biopsies obtained to determine if hCC deposits were reduced following NAC treatment. Remarkably, ~50-90% reduction of L68Q-hCC staining was observed in five of the treated carriers suggesting that L68Q-hCC is a clinical target for reducing agents.Artic Therapeutics LLC Autonomous Community of Madrid (CAM). Spai

A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries

Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, manifest by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in the cystatin C gene, with contemporary carriers reaching an average age of only 30 years. Here, we report, based both on linkage disequilibrium and genealogical evidence, that all known copies of this mutation derive from a common ancestor born roughly 18 generations ago. Intriguingly, the genealogies reveal that obligate L68Q carriers born 1825 to 1900 experienced a drastic reduction in life span, from 65 years to the present-day average. At the same time, a parent-of-origin effect emerged, whereby maternal inheritance of the mutation was associated with a 9 year reduction in life span relative to paternal inheritance. As these trends can be observed in several different extended families, many generations after the mutational event, it seems likely that some environmental factor is responsible, perhaps linked to radical changes in the life-style of Icelanders during this period. A mutation with such radically different phenotypic effects in reaction to normal variation in human life-style not only opens the possibility of preventive strategies for HCCAA, but it may also provide novel insights into the complex relationship between genotype and environment in human disease

Vísindadagur Keldna 2023

Tilraunastöð Háskóla Íslands í meinafræði að Keldum fagnar sjötíu og fimm ára starfsafmæli í ár. Af því tilefni er ráðstefna/vísindadagur sem fer fram 19. apríl 2023 á bókasafni Tilraunastöðvarinnar. Tilraunastöðin starfar fyrst og fremst sem rannsóknastofa á háskólastigi og er eini vettvangurinn í landinu þar sem rannsóknir, skimunarverkefni og greiningar fara fram á dýrasjúkdómum á mörgum fræðasviðum. Rannsakaðir eru sjúkdómar og smitefni í flestum spendýrategundum Íslands og allmörgum fugla-, fisk- og lindýrategundum. Tilraunastöðin er í nánu samstarfi við atvinnulífið, má þar nefna landbúnað, fiskeldi, matvælaframleiðslu og líftækniiðnað. Starfið er rótgróið og gott dæmi um samlegðaráhrif vísindastarfs og atvinnulífs. Vel hefur gengið að vinna með þær sérstöku aðstæður sem eru á Íslandi varðandi dýrasjúkdóma og greiningar á þeim. Vísindadagurinn hefur fest sig í sessi sem vettvangur fyrir kynningu á starfsemi og fræðasviðum Keldna. Ráðstefnan er allan daginn og aðgangur er öllum heimill að kostnaðarlausu. Nú er vísindadagurinn með almennara sniði en oft áður og er m.a. ætlaður sem samráðsvettvangur hagaðila sem starfa í lífvísinda- og dýraheilbrigðisfræðum. Þeir fyrirlesarar sem sjá um fræðsluna eru sérfræðingar á Keldum og aðrir sérfræðingar frá háskólum og vísindastofnunum innanlands og erlendis. Einnig verða kynnt veggspjöld sem greina frá ýmsum verkefnum á Keldum. Anna Karen Sigurðardóttir, Ásthildur Erlingsdóttir og Birkir Þór Bragason eru í vísindanefnd sem sér um undirbúning og skipulag. Ég færi þeim mínar bestu þakkir fyrir spennandi og fjölbreytta dagsskrá. Mínar bestu árnaðaróskir til núverandi og fyrrverandi Keldnastarfsmanna og hamingjuóskir með árangur síðastliðna áratugi. Framlag þeirra hefur gert Keldur að þeirri framsýnu rannsóknastofnun dýrasjúkdóma sem hún er í dag. Á Keldum er fagleg forysta á ýmsum fræðasviðum og mikil þekking og reynsla. Ég óska Tilraunastöðinni og starfsmönnum hennar áframhaldandi velgengni og velfarnaðar í framtíðinni. Sigurður Ingvarsson, forstöðumaður og prófesso

Pathological changes in basement membranes and dermal connective tissue of skin from patients with hereditary cystatin C amyloid angiopathy.

To access publisher's full text version of this article click on the hyperlink belowHereditary cystatin C amyloid angiopathy (HCCAA) is a genetic disease caused by a mutation in the cystatin C gene. Cystatin C is abundant in cerebrospinal fluid and the most prominent pathology in HCCAA is cerebral amyloid angiopathy due to mutant cystatin C amyloid deposition with associated cerebral hemorrhages, typically in young adult carriers. Analyses of post-mortem brain samples shows that pathological changes are limited to arteries and regions adjacent to arteries. The severity of pathological changes at post-mortem has precluded the elucidation of the evolution of histological changes. Mutant cystatin C deposition in carriers is systemic and has, for example, been described in the skin, suggesting similar pathological mechanisms both in the brain and outside of the central nervous system. The aim of this study was to use skin biopsies from asymptomatic and symptomatic carriers to study intermediate events in HCCAA pathogenesis. We found that cystatin C deposition in minimally affected samples was limited to the basement membrane (BM) between the dermis and epidermis. When the deposits were more advanced, they extended to other BM regions in the skin. Our results showed that the immunoreactivity of the BM protein COLIV was increased to a similar extent in all carrier biopsies and cystatin C deposits were in close association with COLIV. The density of fibroblasts in the upper dermis of carrier skin was increased, whereas the distribution of other cell types examined did not differ compared with control biopsies. COLIV and cystatin C immunoreactivity in carrier biopsies was closely associated with the fibroblasts. The results of this study, in conjunction with our previous results regarding pathological BM changes in leptomeningeal arteries of patients, suggest that BM changes are early and important events in HCCAA pathogenesis that could facilitate cystatin C deposition and aggregation.Icelandic Centre for Research (RANNIS) University of Iceland Research Fund Memorial fund of Hafdis Kjartansdottir Memorial fund of Helga Jonsdottir and Sigurlidi Kristjansson Heilavernd fun

Parenchymal cystatin C focal deposits and glial scar formation around brain arteries in Hereditary Cystatin C Amyloid Angiopathy.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageHereditary Cystatin C Amyloid Angiopathy (HCCAA) is an amyloid disorder in Icelandic families caused by an autosomal dominant mutation in the cystatin C gene. Mutant cystatin C forms amyloid deposits in brain arteries and arterioles which are associated with changes in the arterial wall structure, notably deposition of extracellular matrix proteins. In this post-mortem study we examined the neuroinflammatory response relative to the topographical distribution of cystatin C deposition, and associated haemorrhages, in the leptomeninges, cerebrum, cerebellum, thalamus, and midbrain of HCCAA patients. Cystatin C was deposited in all brain areas, grey and white matter alike, most prominently in arteries and arterioles; capillaries and veins were not, or minimally, affected. We also observed perivascular deposits and parenchymal focal deposits proximal to affected arteries. This study shows for the first time, that cystatin C does not exclusively form CAA and perivascular amyloid but also focal deposits in the brain parenchyma. Haemorrhages were observed in all patients and occurred in all brain areas, variable between patients. Microinfarcts were observed in 34.6% of patients. The neuroinflammatory response was limited to the close vicinity of affected arteries and perivascular as well as parenchymal focal deposits. Taken together with previously reported arterial accumulation of extracellular matrix proteins in HCCAA, our results indicate that the central nervous system pathology of HCCAA is characterised by the formation of a glial scar within and around affected arteries.Icelandic Centre for Research (RANNIS) University of Iceland Research Fund Memorial fund of Hafdis Kjartansdottir Memorial fund of Helga Jonsdottir and Sigurlidi Kristjansson Heilavemd fun

Deposition of collagen IV and aggrecan in leptomeningeal arteries of hereditary brain haemorrhage with amyloidosis.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageHereditary Cystatin C Amyloid Angiopathy (HCCAA) is a rare genetic disease in Icelandic families caused by a mutation in the cystatin C gene, CST3. HCCAA is classified as a cerebral amyloid angiopathy and mutant cystatin C forms amyloid deposits in cerebral arteries resulting in fatal haemorrhagic strokes in young adults. The aetiology of HCCAA pathology is not clear and there is, at present, no animal model of the disease. The aim of this study was to increase understanding of the cerebral vascular pathology of HCCAA patients with an emphasis on structural changes within the arterial wall of affected leptomeningeal arteries. Examination of post-mortem samples revealed extensive changes in the walls of affected arteries characterised by deposition of extracellular matrix constituents, notably collagen IV and the proteoglycan aggrecan. Other structural abnormalities were thickening of the laminin distribution, intimal thickening concomitant with a frayed elastic layer, and variable reduction in the integrity of endothelia. Our results show that excess deposition of extracellular matrix proteins in cerebral arteries of HCCAA is a prominent feature of the disease and may play an important role in its pathogenesis.Icelandic Centre for Research (RANNIS) University of Iceland Research Fund Icelandic Centre for Research - Student's Innovation Fund Heilavernd fund Memorial fund of Hafdis Kjartansdottir Memorial fund of Helga Jonsdottir and Sigurlidi Kristjansso

NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients

Funding Information: We thank all the patients involved in this study for their participation. Funding for this work was provided by an Institutional Development Fund to the Center for Applied Genomics from Children’s Hospital of Philadelphia and a sponsored Research agreement with Artic Therapeutics LLC. Funding was provided to Dr. Gutierrez-Uzquiza from Autonomous Community of Madrid (CAM). Spain. “2017-T1/BMD-5468” 2018-2020.-IP: Alvaro Gutierrez Uzquiza. Publisher Copyright: © 2021, The Author(s).Hereditary cystatin C amyloid angiopathy is a dominantly inherited disease caused by a leucine to glutamine variant of human cystatin C (hCC). L68Q-hCC forms amyloid deposits in brain arteries associated with micro-infarcts, leading ultimately to paralysis, dementia and death in young adults. To evaluate the ability of molecules to interfere with aggregation of hCC while informing about cellular toxicity, we generated cells that produce and secrete WT and L68Q-hCC and have detected high-molecular weight complexes formed from the mutant protein. Incubations of either lysate or supernatant containing L68Q-hCC with reducing agents glutathione or N-acetyl-cysteine (NAC) breaks oligomers into monomers. Six L68Q-hCC carriers taking NAC had skin biopsies obtained to determine if hCC deposits were reduced following NAC treatment. Remarkably, ~50–90% reduction of L68Q-hCC staining was observed in five of the treated carriers suggesting that L68Q-hCC is a clinical target for reducing agents.Peer reviewe