Molecular pathogenesis of subarachnoid haemorrhage Baiping Zhang, Kaare Gugleholm, Lorna B. Day, Shu Ye, Roy O. Weller, Ian N.M. Day 5 November 2002

Pathogenesis and the stages involved in the formation of saccular aneurysm Cellular and molecular architecture of the vessel wall Molecular pathology PKD1 gene and polycystin COL3A1 and type III collagen Fibrillin-1 Collagen IV and other basement membrane constituents Alpha1-Antitrypsin (protease inhibitor) Future focus

Subarachnoid haemorrhage (SAH) Condition caused by the escape of blood from a cerebral artery into the subarachnoid space along the surface of the brain.

Mortality of diagnosed cases is about 40% within the first 30 days Less then 25% have a good functional outcome and the disease has dramatic impact on the lives of carers and relatives. Pritchard, Foulkes, Lang, & Neil-Dwyer. 2001

Schematic overview of contributory factors to subarachnoid haemorrhage B. Zhang et al./ The International Journal of Biochemistry & Cell Biology 35 (2003)

Commonest sites for Saccular Aneurysms B. Zhang et al./ The International Journal of Biochemistry & Cell Biology 35 (2003)

Etiology involved in the formation of saccular aneurysms Majority of aneurysms occur between the ages of 40 and 70 Ageing effects on the arteries Increased incidence of saccular aneurysms in families with Polycystic kidney disease Fibromuscular dysplasia Moyamoya disease Marfan Syndrome EDS type IV

PKD1 gene and polycystin Adult polycystic kidney disease is an autosomal dominant disorder in which renal cysts form, leading to progressive loss of glomerular filtration and subsequently to renal failure and end-stage renal disease. PKD1 gene causing (PKD) Encodes for a protein named polycystin Polycystin - participates in protein-protein and protein-carbohydrate interactions in the extracellular matrix adpkd.cimr.cam.ac.uk/ buttons/pkd1_hs_350.gif

COL3A1 and type III collagen Ehlers-Danlos Syndrome Vascular Type Arterial rupture risk Thin transparent skin Early bruising Joint laxity Ligament weakness Bowel rupture (EDS type IV) Defective collagen III synthesis Vascular expression on COL3A1

Collagen IV and other basement membrane constituents Collagen IV defects cause Alport’s syndrome. Alports syndrome characterized sensorineural hearing loss and haematuria. Its is therefore plausible new hypothesis that defects in the basement membrane as well as defects in the elastic and medial layer may predispose intracranial aneurysms

Protease inhibitor (alpha1- Antitrypsin) Most abundant and potent natural inhibitor of elastase. Alpha1-Antitrypsin activity has been claimed to be reduced in both intracranial and abdominal aortic aneurysm.

Future focus

Fibrillin-1 and FBN1 Marfan syndrome is an autosomal dominant heritable disorder of connective tissue with prominent manifestations affecting the skeletal, ocular and cardiovascular systems. Progressive dilation of the aortic root and aortic dissection and rupture are frequent, and mitral and aotic valve insufficiency may also occur early. Caused by mutations in FBN1 gene encoding fibrilin-1 Mutations of this gene also cause type I fibrillinopathies