Sunday, May 6, 2012

Range of brain diseases Prion, Parkinson's, Alzheimer's could be treated by single drug

Range of brain diseases could be treated by single drug

Brain cells
Can brain cell death be prevented in a range of diseases?

The tantalising prospect of treating a range of brain diseases, such as Alzheimer's and Parkinson's, all with the same drug, has been raised by UK researchers.

In a study, published in Nature, they prevented brain cells dying in mice with prion disease.

It is hoped the same method for preventing brain cell death could apply in other diseases.

The findings are at an early stage, but have been heralded as "fascinating".

Many neuro-degenerative diseases result in the build-up of proteins which are not put together correctly - known as misfolded proteins. This happens in Alzherimer's, Parkinson's and Huntington's as well as in prion diseases, such as the human form of mad cow disease.

Turn off

Researchers at the University of Leicester uncovered how the build-up of proteins in mice with prion disease resulted in brain cells dying.

They showed that as misfolded protein levels rise in the brain, cells respond by trying to shut down the production of all new proteins.

It is the same trick cells use when infected with a virus. Stopping production of proteins stops the virus spreading. However, shutting down the factory for a long period of time ends up killing the brain cells as they do not produce the proteins they actually need to function.

“Start Quote

There are good reasons for believing this response, identified with prion disease, applies also to Alzheimer's and other neuro-degenerative diseases”

End Quote Prof Roger Morris King's College London

The team at the Medical Research Council laboratory in Leicester then tried to manipulate the switch which turned the protein factory off. When they prevented cells from shutting down, they prevented the brain dying. The mice then lived significantly longer.

Each neuro-degenerative disease results in a unique set of misfolded proteins being produced, which are then thought to lead to brain cells dying.

Prof Giovanna Mallucci told the BBC: "The novelty here is we're just targeting the protein shut-down, we're ignoring the prion protein and that's what makes it potentially relevant across the board."

The idea, which has not yet been tested, is that if preventing the shut down protects the brain in prion disease - it might work in all diseases that have misfolded proteins.

Prof Mallucci added: "What it gives you is an appealing concept that one pathway and therefore one treatment could have benefits across a range of disorders.

"But the idea is in its early stages. We would really need to confirm this concept in other diseases."


Alzheimer's brain on the left showing shrinkage, with a healthy brain on the right

The study has been broadly welcomed by other scientists although many point out that the research is in its infancy.

Professor of Molecular Neurobiology at King's College London, Roger Morris, said it was a "breakthrough in understanding what kills neurons".

He added: "There are good reasons for believing this response, identified with prion disease, applies also to Alzheimer's and other neuro-degenerative diseases.

"And because it is such a general response, we already have some drugs that inhibit this response."

Prof Andy Randall, from the University of Bristol, said: "This is a fascinating piece of work.

"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.

"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."

Dr Eric Karran, the director of research at Alzheimer's Research UK, said: "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."

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Julie A. Moreno,1

Journal name:
Year published:

Published online

The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer’s, Parkinson’s and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the α-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2α-P levels are seen in patients with Alzheimer’s, Parkinson’s and prion diseases1, 2, 3, 4, but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2α-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2α-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2α-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2α-P dephosphorylation5, increased eIF2α-P levels, exacerbating neurotoxicity and significantly reducing survival in prion-diseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.