Pathomolecular mechanisms of intracerebral haemorrhage: functional analysis of collagen IV variants.

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Each year, 150,000 people in the UK have a stroke, which is a major cause of death and disability. There are two types of stroke: those caused by blocked blood vessels and those due to rupture of blood vessels resulting in a brain bleed (haemorrhagic stroke). Intracerebral haemorrhage (brain bleeding), accounts for 15% of all adult strokes, carries the worst prognosis and there are no specific treatments for intracerebral haemorrhage, in part because we do not understand the causes of this disease.The "basement membrane" is a structure that forms outside of cells and provides strength to blood vessels by acting as a permanent scaffold in the walls of blood vessels. Two collagen proteins produced from genes named COL4A1 and COL4A2 are major components of this basement membrane. We have found that defects in these genes, called "mutations," cause rare inherited forms of haemorrhagic stroke that affects multiple people within a family. Collagen is produced and folded inside cells and then moved out of cells. Our work suggests that these rare mutations affect basement membrane integrity but also have their damaging effects by causing incorrect folding of the COL4A1 and COL4A2 proteins. These misfolded collagen proteins then accumulate inside cells and causes these cells to become "stressed", which interferes with their function.Excitingly, our new data suggest that changes in these collagen genes, which occur frequently in the population, are a risk factor for intracerebral haemorrhage in the general population. This raises several important questions: 1) How many stroke patients are affected by these common gene changes? 2) How do the changes that occur in the general population cause bleeding, and does their mechanism involve the accumulation of protein within cells and cell stress, similar to the rare inherited mutations?To answer these questions we will analyse the COL4A1 and COL4A2 genes in DNA samples from a large number of patients from the general population that have had an intracerebral haemorrhage. By identifying the changes that occur in these genes we will determine the proportion of patients in whom altered collagen IV genes contribute to stroke. We will use computer analysis to predict whether the identified alterations affect the amount of collagen produced or may lead to changes in protein structure, similar to what occurs with mutations in the rare inherited forms of intracerebral haemorrhage. For some of the changes identified, we will then directly determine whether they lead to accumulation of collagen and "stress" inside blood vessel cells and establish their effects on the composition of the basement membrane. We will then investigate how the cell stress and basement membrane defects affect the health and function of these cells. Finally, we will determine if this cell stress response, basement membrane defects and other identified defects from blood vessels cells occur in brain samples. By combining DNA analysis with investigations in cells and brains, we will obtain a much better understanding of how intracerebral haemorrhage develops. This will aid in the long term the development of new and/or more effective therapies for intracerebral haemorrhaging. By identifying the proportion of intracerebral haemorrhage patients in which these collagen changes occur and determining if all changes act in the same way, our results can indicate if a future "one version fits all" therapy is likely to be feasible and we will learn for how many patients these treatments may be effective. Interestingly, some drugs that are used to treat other diseases can reduce stress in cells grown in the laboratory, which would allow relative rapid progress to be made in developing treatments for stroke.