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A study in mice suggested a common mechanism underlying nerve cell death in neurodegenerative diseases like Alzheimer’s, Parkinson’s and prion diseases. Published in Nature, the study suggests an avenue to develop treatments for these diseases.
Derek Hill, Professor of Medical Imaging Sciences, University College London and CEO of IXICO, said:
“Over the last decade, many different approaches to slowing down or reversing dementia have been tried. None have yet been shown to work in humans, even though they often looked promising in tests on mice. This paper shows some promising results from a new potential treatment approach. This is welcome, and new approaches are needed. However, it will take many years to determine whether this type of treatment is safe and effective in humans with neurodegenerative diseases.”
Dr Eric Karran, Director of Research at Alzheimer’s Research UK, said:
“While neurodegenerative diseases can have many different triggers, this study suggests that they may act through a common mechanism to damage nerve cells. The findings present the appealing concept that one treatment could have benefits for a range of different diseases; however the idea is in its early stages. The research focuses on the effects of the prion protein and we would need to see the same results confirmed in Alzheimer’s and Parkinson’s to really strengthen the evidence.
“Understanding more about what goes so wrong in neurodegenerative diseases is vital for the development of effective new treatments. With diseases such as Alzheimer’s and Parkinson’s affecting huge numbers of people across the world, we must invest in research now.”
Roger Morris, Professor of Molecular Neurobiology and Head, School of Biomedical Sciences, King’s College London, said:
“Alzheimer’s and Parkinson’s are common examples of neurodegenerative diseases. In these diseases, neurons in the brain die, destroying the patient’s brain from inside.
“Why neurons die in these diseases has remained an unsolved mystery, and therefore a major obstacle to devising effective treatments, or to understanding how to diagnose these debilitating illnesses at early stages when therapies could be effective.
“Professor Giovanna Mallucci and colleagues at the Medical Research Council’s Toxicology Unit in Leicester announce in this week’s Nature a major breakthrough in understanding what kills neurons in neurodegenerative disease.
“They study ‘prion’-driven neurodegeneration, the active agent in ‘mad cow disease’ or Creutzfeld-Jacob Disease in man, which appears to involve very similar mechanisms to Alzheimer’s Disease. But, unlike AD, prion diseases can be accurately studied in experimental mice, allowing the very early stages of the disease to be identified.
“Mallucci’s group finds that neurons in the brain respond to prion infection by the same mechanism that all the cells of our bodies use to fight viral infection: they shut down the production of all proteins.
For viruses, the failure to produce viral proteins stops propagation of the virus, which is a good thing.
For neurons, failure to produce any new proteins slowly kills the neurons, which is not a good thing.
“This activation by neurons of a general protective response of all cells leads to a very non-protective result – the slow death of the brain. There are good reasons for believing this response, identified with prion disease, applies also to Alzheimer’s and other neurodegenerative diseases.
“And because it is such a general response, we already have some drugs that inhibit this response.
“These drugs are not what you should take when you have a bad cold or other viral infection but, once adapted to work within the brain, they may protect against the ravages of neurodegenerative diseases.”
Andy Randall, Professor of Applied Neurophysiology, University of Bristol, said:
“This is a fascinating piece of work highlighting a pathway involved in producing brain damage in prion disease. Prion diseases are examples of range of degenerative CNS diseases characterised by atypical protein deposits. It will be interesting to see if similar processes occur in some of the common diseases with such deposits, for example Alzheimer’s and Parkinson’s disease. It is easy to see from this exciting study how this could be done, and I am sure such studies will be taken on by laboratories around the world who are interested in developing therapies for various neurodegenerative conditions.”
Additional comment and background from Andy Randall: “A pathological feature shared by many degenerative diseases, including those of the CNS, is the build-up of misfolded protein aggregates. It has long believed that these play a role in producing disease phenotypes including cell death. In this interesting new paper, Moreno et al. provide experimental evidence for a cellular pathway through which misfolded proteins may produce damage to the central nervous system. “This group from Leicester, along with collaborators from Nottingham and Cambridge, have been investigating prion disease in mice (a mouse equivalent of CJD in man), for which there is a very convenient experimental model in which a rapidly and substantial degenerative brain disease arises. In this model, as in human disease, the cellular prion protein gets misfolded into a toxic form which aggregrates and produces damage to brain cells. Their work indicates that the toxic form of prion protein triggers a signalling cascade inside neurones that inhibits the production of an array proteins, including proteins pivotally involved in synaptic function. This down-regulation of protein production has probably evolved to be a protective mechanism designed to allow cells gummed up with misfolded proteins to sort themselves out. “However, this pathway is one that cannot be employed for too long, since a lack of production of key proteins will eventually be detrimental to neurones- and this is what seems to happen in prion disease (an analogy here is that someone who is obese could benefit from greatly reducing food intake, however, not for too long as they will eventually starve). Inhibiting the pathway that down-regulates protein production protects mice from prion disease, as measured in multiple ways, including cell death, damage to synapses and their function and behaviour. Contrariwise, pharmacologically enhancing activity in the pathway makes things worse. “So, inhibiting this pathway that reduces protein synthesis may help to reduce the CNS damage caused by prion diseases, but these diseases, although devastating, are very rare in humans, with CJD being the most prevalent occurring in only about 1 in a million people per year. The burning question posed by this work is are similar mechanisms engaged in more common neurodegenerative diseases characterised by pathological protein deposits, for example Alzhiemer’s disease, Parkinson’s disease and Huntington’s disease? “Furthermore, if this is the case, can modulating this same pathway be a route to new therapeutic approaches in these more prevalent conditions that afflict many millions of sufferers around the world. Ultimately only more research will tell us this. Helpfully, mouse models of many of these diseases are already established and characterised, meaning the hypothesis can be tested, and the exciting work of Moreno and colleagues on prion disease provides an excellent guide as to how to perform the required work.”
John Hardy, Professor of Neuroscience, University College London, said:
“This is an interesting paper but it only deals with prion disease. It’s important that basic research such as this is not presented as fresh hope for new treatments for devastating diseases such as Alzheimer’s disease and Parkinson’s disease.”
‘Sustained translational repression by eIF2a-P mediates prion neurodegeneration’ by Moreno, P. et al., published in Nature on Sunday 6th May.