Mechanisms for limiting haemoglobin toxicity during red blood cell development
Mammalian adult haemoglobin (Hb) A is a tetramer of 2 &alpha-Hb and 2 &beta -Hb protein subunits. &beta -Thalassaemia is a genetic disorder caused by mutations that reduce the expression of &beta -Hb leading to anaemia. In addition to reduced &beta -Hb expression, there is a relative excess of &alpha-Hb, which is toxic to red blood cells, primarily due to the catalytic production of reactive oxygen species (ROS). Currently, the only commonly available treatment for thalassaemia is regular and life-long blood transfusion, requiring regular hospitalisation and daily drug administration. An exciting prospective therapy is to replace the defective marrow with cultured host stem cells into which a functional &beta -Hb gene has been introduced, but to date no successful treatment has been developed. One of the major hurdles is to achieve appropriate and stable expression levels of the introduced gene.
By combining structural methods with biochemistry and mouse genetics we have discovered that &alpha-Hb stabilizing protein (AHSP: yellow above) specifically binds &alpha-Hb (grey) and protects cells from the toxic effects of free globin chains through a number of mechanisms. One mechanism involves the conversion of the haem group to a bis-histidyl coordination geometry (above right) that reduces redox cycling.
We believe that up-regulating AHSP may synergise with globin gene therapy by buffering cells against any residual globin chain imbalances.
- Dr David Gell (Member)
- Claire Dickson (PhD Candidate)
- Kaavya Krishna Kumar (PhD Candidate)