Pálsdóttir Group: Hereditary brain hemorrhage

Address

Keywords

brain hemorrhage, cystatin C, parent-of-origin effect, environmental effect, phenotypic plasticity

Models

dermal fibroblast, zebrafish

Techniques

cell culture, molecular biology, RNA sequencing, proteomics, Immunohistochemsitry

Collaborations outside COST

The Hertie Institute, University of Tubingen, Germany. Group of Mathias Jucker. University of Manchester UK. Group of Garth Cooper. Center for Applied Genomics, Childrens´Hospital of Philadelphia, USA. Group of Hakon Hakonarson

Short description of ongoing research projects

We are studying a dominantly inherited disease caused by a mutation in the cystatin C gene. The mutated protein gets deposited as amyloid in brain arterioles. Carriers get brain hemorrhages as young adults but few have late onset. A maternal effect is seen where those who inherit the gene from the mother die 9.5 years younger compared to those who got it from their father. By tracing all subfamilies back in time an environmental effect became clear. Before 1820 carriers were not affected by the mutation but thereafter carriers started to the get brain hemorrhages. Around 1900 the lifespan was down to 30 years and has been stable since. Import records for the whole of Iceland showed a big increase in sugar/grain import after 1820 suggesting an environmental effect on penetrance. We have studied the transcriptosome of the dermal fibroblasts of carriers and controls and see more ECM production in carriers. This is supported by IHC of patients´ brains. We are studying the effects of HDAC inhibitors on the gene activity of carriers. We are establishing a zebra fish model of the disease.

Publications

1. Snorradottir AO, Isaksson HJ, Kaeser SA, Skodras AA, Olafsson E, Palsdottir A, Bragason BT (2015). Parenchymal cystatin C focal deposits and glial scar formation around brain arteries in Hereditary Cystatin C Amyloid Angiopathy. Brain Research; 1622: 149-162.
2. Snorradottir AO, Isaksson HJ, Kaeser SA, Skodras AA, Olafsson E, Palsdottir A, Bragason BT (2013). Deposition of collagen IV and aggrecan in leptomeningeal arteries of hereditary brain hemorrhage with amyloidosis. Brain Research; 1535: 106-14.
3. Palsdottir A, Helgason A, Palsson S, Bjornsson HT, Bragason BT, Gretarsdottir S, Thorsteinsdottir U, Olafsson E, Stefansson K. (2008). A drastic reduction in the life span of cystatin C L68Q carriers due to life-style changes during the last two centuries. PLoS Genet. 2008 Jun 20;4(6):e1000099.
4. Palsdottir A, Snorradottir AO, Thorsteinsson L, (2006) Hereditary cystatin C amyloid angiopathy: genetic clinical and pathological aspects. Brain Pathology, 16:55-59.

Other activities of potential interest to others