Understanding and Treatment of Hutchinson-Gilford Progeria Syndrome
SPARKs Children’s Charity, Progeria Research Fund, Brunel University
Hutchinson-Gilford Progeria Syndrome (HGPS) is a fatal, devastating disease of children caused usually by a de novo mutation in the gene encoding the nuclear structural protein lamin A. In classical HGPS this mutation leads to the presence of a cryptic splice site that leads to the pre-lamin A protein being truncated and interferes with the processing creating a toxic protein called progerin. Our findings have revealed that these cells readily go through apoptosis, accumulate nuclear aberrations as they age (Bridger and Kill 2004) and have abnormal distributions of nuclear proteins such as nuclear motor proteins and nucleoli (Mehta et al., 2010; Mehta et al., 2011).
The HGPS cells also display an abnormal distribution of chromosomes and resemble quiescent cells even though they are displaying proliferative markers (Meaburn et al., 2007; Mehta et al., 2011). The mislocalisation of lamins can be restored with a range of drugs but only farnesyltransferase inhibitors (FTIs) can restore the chromosome positioning to normal (Mehta et al., 2011; Clements/Bikkul et al., in prep 2017).
Another aspect of the HGPS cells is that they display large amounts of DNA damage. The best drug in our hands out of a large panel for correcting this DNA damage is rapamycin. We visualised the damage using COMET assays employing an automatic COMET imaging and analysis programme (Clements/Kill et al., man in prep 2017).
Principal Investigator: Joanna Bridger
Co- Investigators: Dr Craig Clements, Dr Mehmet Bikkul, Dr Gemma Worthington, Dr Pravin Badhe, Dr Ian Kill