Scientists at the Medical Research Council Laboratory of Molecular Biology – based in Cambridge, UK – have successfully targeted an enzyme involved in cell signalling that could reduce the number of Huntington’s Disease-associated proteins found in mouse brains.
For the characteristics of proteins to be expressed, they must be turned ‘on’ by kinases – an enzyme that attaches a phosphate group to the specific protein. Another family of enzymes called phosphatases turn the signal ‘off’ by removing the phosphate group.
Unlike kinases, phosphatases are difficult to selectively target, as the functional part of the enzyme that removes the phosphate group is common across the family. Due to this feature, drugs that target phosphatases can lead to side effects.
‘For decades, with no way to selectively target phosphatases, research into them has lagged behind kinases and they’ve been described as “undruggable”,’ said study-leader Dr Anne Bertolotti. ‘Our new system is only a first step, but we hope cracking this problem will stimulate phosphatase research and drug development.’
The team’s new system creates synthetic phosphatases that are connected to chips that can be screened to find a specific molecule match that could be used therapeutically.
‘Targeting phosphatases – instead of kinases – is like targeting the brake, rather than the accelerator, on signals in cells,’ she said. ‘By inhibiting a phosphatase, we prolong a signalling event that has already been turned on, which may offer safer ways to specifically after signalling in cells and help to create new drugs with fewer side-effects.’
Using this method, the group discovered Raphin1, which reduced the accumulation of misfolded proteins known to cause Huntington’s Disease, and specifically targeted the gene that expresses phosphatase involved – PPP1R15B.
‘Since Huntington’s disease runs in families and can be diagnosed genetically, early diagnosis could provide what we hope is a window of opportunity to target the disease before symptoms appear,’ Dr Bertolotti noted. ‘Our unique approach manipulates cells to slow down normal functions and give them a chance to clear up the misfolded proteins that are characteristic of Huntington’s.
‘However, it will take some years before we know if this approach works in humans and is safe.’
By Georgina Hines