By Murat Emre
Recently researchers from the MRC Toxicology Unit based at the University Of Leicester provided “food for hope.” Moreno et al reported in Science Translational Medicine that an oral treatment targeting the “unfolded protein response” prevented neurodegeneration and clinical disease in an animal model — in “prion-infected mice,” a model of prion diseases which occur also in humans. In their approach the researchers exploited the natural defence mechanisms built into brain cells. When a virus penetrates a brain cell, it uses the cell’s own machinery to produce viral proteins. As a defensive response cells shut down nearly all protein production in order to stop the virus’s spread.
During prion disease, an increase in misfolded prion protein leads to over-activation of the so-called “unfolded protein response” (UPR) that controls the initiation of protein synthesis. This results in persistent repression of protein synthesis and the loss of critical proteins for cell functioning, leading to neuronal death. In their experiment the researchers showed that oral treatment with a specific inhibitor of a key enzyme for the UPR pathway prevented repression of protein synthesis and development of clinical symptoms of the disease with preservation of nerve cells. Importantly, this enzyme inhibitor acts downstream, that is, it was effective despite continuing accumulation of misfolded prion protein. These data suggest that this enzyme, and potentially other members of this pathway, may be new therapeutic targets for developing drugs against prion disease or some other neurodegenerative diseases.
This is the first time that a compound prevented neurodegeneration in a living animal. What does this mean for neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), in which there is slowly progressing and selective loss of neurons? Many such diseases involve production of faulty or “misfolded” proteins. These “bad” proteins which can not be cleared by other mechanisms activate the same defence system as described above with grave consequences: the brain cells shut down protein production, depriving themselves from vital proteins and eventually leading to cell death. This process is thought to take place in many forms of neurodegeneration, therefore disrupting it could theoretically treat such diseases. This provides drug developers a new mechanistic pathway to work on, which may eventually yield neuroprotective drugs. Their use can halt disease progression; patients treated early may not progress and may not develop advanced stages of the disease or their complications such as dementia in PD.
This is a very exciting development, but we are still far from its application in humans. First these results need to be replicated including animal models of AD and PD. In parallel, compounds should be developed which can safely be administered in humans and that are specific for brain, then clinical trials may start which may take 5-10 years. Drug development in neurodegenerative diseases has witnessed many disappointments: compounds with dramatic effects in animal models ended up being dramatic failures in clinical trials. Along with efficacy, safety is an issue, in particular with enzyme inhibitors; this compound had untoward effects on the pancreas and mice developed a mild form of diabetes.
Despite the long way to go, this new finding gives enough reason for excitement. A drug which targets a mechanism common to a number of neurodegenerative diseases may be too good to be true, but after all, innovation starts with novel ideas, which first needs mechanistic proof of concept. That first step seems to be taken.
Murat Emre is Professor of Neurology at the Istanbul Faculty of Medicine, Istanbul, Turkey. He is the author of Cognitive Impairment and Dementia in Parkinson’s Disease published by Oxford University Press.