The complexity of neurodegenerative diseases like PSP and CBD means that, en route to developing effective treatments, researchers need to unpick the individual mechanisms that are going wrong in nerve cells.
Dr Rohan de Silva at the Institute of Neurology in London has recently completed a project, funded by the PSPA, to better understand how a protein called PERK might influence the clumping of tangled tau protein we know to be associated with the demise of neurons in PSP.
PERK is involved in helping cells to deal with uncontrolled protein clumping and there is already evidence that problems with PERK might exacerbate tau build-up. A particular variation in the genetic code for PERK appears to be associated with a slightly increased risk of PSP.
Throughout the course of the project Dr de Silva, assisted principally by PhD student Bimali Hapuarachchi, has developed a simple biological model consisting of cells that contain different forms of the PERK protein, as coded for by different variants of the gene. This work alone has provided an extremely useful platform for further investigation, but along the way the researchers also discovered that the form of PERK produced by the risk-associated version of its gene displayed significantly reduced activity. This could have a significant bearing on tau accumulation and suggests a possible basis as to how the PERK gene variation contributes to disease risk.
The cell models now give provide the opportunity to investigate further how PERK variants contribute to PSP and, more importantly, how the deleterious aspects can be reduced or reversed. Dr de Silva intends to examine what happens if the cell models are made to generate high levels of normal and abnormal tau and how the different forms of PERK influence the cell’s response and subsequent tau accumulation. This is an early step on the road to the development of new drugs that may eventually treat PSP through their impact on PERK activity.