Moreno JA, Halliday M, Mooloy C, et al. Oral Treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice.Sci. Transl. Med. 5, 206ra138 (2013)
http://stm.sciencemag.org/content/5/206/206ra138
It will have been hard to avoid news of this study - the popular press as well as the neuroscience world has been swept up in the exciting possible implications of the article by Julie Moreno et al. We at PREDICT-PD are also cautiously optimistic about the results they report and the potential for developing a treatment to prevent the neurodegeneration seen in Parkinson's Disease as well as other diseases such as Alzheimer's. But we are still a long way from any disease modifying treatment, and it's worth having a closer look at the study to pick apart what they've really demonstrated.
What did they do?
The authors used an oral treatment in a mouse model of prion disease*. Whilst prion diseases have some similarity to Parkinson's Disease in that they both involve misfolded versions of normal proteins (the prion protein in prion disease and alpha synuclein in PD), they are certainly not the same. Whilst both cause neurodegeneration, prion diseases usually progress far more quickly, suggesting that the mechanisms causing cell death in these conditions may be quite different. The hallmark of prion diseases is their ability to be transmitted between organisms, with the protein itself being the infective agent and causing abnormal folding in other proteins. Some researchers have suggested that Parkinson's disease may share similar features (Olanow and Brundin, 2013), but this is still a controversial view. In any case, we should be very careful before extrapolating these results from prion disease to PD or other common neurodegenerative diseases.
What did they test?
The compound, which has the catchy name "GSK2606414", is an inhibitor of PERK (protein kinase RNA–like endoplasmic reticulum kinase). To understand what PERK does, and why inhibiting it might prevent neurodegeneration, a bit of biology:
Bip = binding immunoglobulin, eIF2 = eukaryotic initiation factor 2
When brain cells notice that proteins are not folding correctly, they respond by activating the above pathway and reducing the amount of protein produced (presumably a protective mechanism). However, if protein translation is reduced by too much, neurons may be unable to synthesise the important proteins they need for their funciton and survival. The authors of this paper had previously shown that this is what goes wrong in prion disease and that blocking this pathway could be protective (Moreno et al, 2012).
Interestingly, increased levels of both PERK and eIF2 have also been found in the brains of patients with Parkinson's (Hoozemans et al, 2007), implicating pathological activation of this pathway as an aspect of the neurodegenerative process, so it certainly seems to be a rational drug target in PD too.
What was the compound shown to do?
Importantly, the authors first showed that the compound penetrates the blood brain barrier, so would be available to work where it is needed.
The drug reduced the signs of prion disease in the mice and resulted in behavioural improvements. The mice treated with GSK2606414 showed less hindlimb paralysis (an important sign of prion disease) and better mobility than those who did not receive the treatment. Although dementia and memory loss are difficult to assess in mice, the authors demonstrated that the treated mice performed better in a simple memory test and that they burrowed more than the untreated animals (mice with neurodegenerative diseases have been shown to burrow less).
Not only did the drug result in behavioural improvements but it was also truly neuroprotective: it halted the death of neurons across the brain. Finally, analysis of samples of the mice brains revealed that the drug was acting via the molecular pathways expected of it; the drug inhibited PERK activation and restored the translation of important proteins, exactly as it was designed to.
Even if this treatment does prove to be effective in animal models of Alzheimer’s or Parkinson’s disease, there is no guarantee it will work in humans. Countless drug trials for these diseases have failed over the last ten years, even after encouraging results in animal trials, so there is reason to remain cautious. If the drug proves to be safe in humans, there will be important questions to be answered about when it is given - presumably treatment would need to start early in the disease process to prevent neurodegeneration before it becomes disabling. As we've previously discussed, in PD a significant amount of neurodegeneration occurs before the diagnosis is made, suggesting that even at diagnosis may be too late.
Nonetheless, this is the first time an oral treatment has been shown to completely stop neurodegeneration in its tracks and it represents an important step forward in the search for a definitive treatment for both Parkinson's disease and Alzheimer's disease.
- Anna and Joe
Jargon buster:
Prion diseases are a group of rare progressive neurodegenerative disorders caused by abnormal, misfolded proteins called prions. They are transmissable (can be spread from person to person), but most cases are sporadic.
Translation is the stage of protein production in which single amino acids are put together to form a polypeptide (protein).
Hyperglycaemia: high blood sugar levels (which is what occurs in diabetes).
____
Hoozemans JJ, van Haastert Es, Nijholt DA, et al. Activation of the unfolded protein response in Parkinson's disease. Biochem. Biophys. Res. Commun. 354, 707-711 (2007)
Olanow CW, Brundin P. Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder? Mov. Disord. 28(1), 31-40 (2013)
Moreno JA, Radford H, Peretti D, Steinert JR, Verity, N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori C, Barrett A, Tsaytler P, Bertolotti A, Willis AE, Bushell M, Malluci GR, Sustained translational repression by eIF2a-P mediates prion neurodegeneration. Nature 485, 507-511 (2012)
http://stm.sciencemag.org/content/5/206/206ra138
What did they do?
The authors used an oral treatment in a mouse model of prion disease*. Whilst prion diseases have some similarity to Parkinson's Disease in that they both involve misfolded versions of normal proteins (the prion protein in prion disease and alpha synuclein in PD), they are certainly not the same. Whilst both cause neurodegeneration, prion diseases usually progress far more quickly, suggesting that the mechanisms causing cell death in these conditions may be quite different. The hallmark of prion diseases is their ability to be transmitted between organisms, with the protein itself being the infective agent and causing abnormal folding in other proteins. Some researchers have suggested that Parkinson's disease may share similar features (Olanow and Brundin, 2013), but this is still a controversial view. In any case, we should be very careful before extrapolating these results from prion disease to PD or other common neurodegenerative diseases.
What did they test?
The compound, which has the catchy name "GSK2606414", is an inhibitor of PERK (protein kinase RNA–like endoplasmic reticulum kinase). To understand what PERK does, and why inhibiting it might prevent neurodegeneration, a bit of biology:
When brain cells notice that proteins are not folding correctly, they respond by activating the above pathway and reducing the amount of protein produced (presumably a protective mechanism). However, if protein translation is reduced by too much, neurons may be unable to synthesise the important proteins they need for their funciton and survival. The authors of this paper had previously shown that this is what goes wrong in prion disease and that blocking this pathway could be protective (Moreno et al, 2012).
Interestingly, increased levels of both PERK and eIF2 have also been found in the brains of patients with Parkinson's (Hoozemans et al, 2007), implicating pathological activation of this pathway as an aspect of the neurodegenerative process, so it certainly seems to be a rational drug target in PD too.
What was the compound shown to do?
Importantly, the authors first showed that the compound penetrates the blood brain barrier, so would be available to work where it is needed.
The drug reduced the signs of prion disease in the mice and resulted in behavioural improvements. The mice treated with GSK2606414 showed less hindlimb paralysis (an important sign of prion disease) and better mobility than those who did not receive the treatment. Although dementia and memory loss are difficult to assess in mice, the authors demonstrated that the treated mice performed better in a simple memory test and that they burrowed more than the untreated animals (mice with neurodegenerative diseases have been shown to burrow less).
 |
| When rodents are left with a tube full of food pellets (as shown above), it is their natural tendency to burrow into the food. The pellets displaced from the tube after 2 hours are weighed and recorded. Mice with neurodegenerative diseases are known to burrow less, but the mice given the treatment burrowed as normal. |
Not only did the drug result in behavioural improvements but it was also truly neuroprotective: it halted the death of neurons across the brain. Finally, analysis of samples of the mice brains revealed that the drug was acting via the molecular pathways expected of it; the drug inhibited PERK activation and restored the translation of important proteins, exactly as it was designed to.
So what's not to like?
As previously mentioned, the compound was tested in a mouse model of prion disease, which, despite its similarities with PD, is not the same disease. In addition, the mice suffered from side effects (specifically, weight loss and hyperglycemia*) likely due to effects of the drug outside the brain. Development of the compound to reduce side effects, perhaps by targetting neurons more specifically, would would be necessary before it moves into human trials.Even if this treatment does prove to be effective in animal models of Alzheimer’s or Parkinson’s disease, there is no guarantee it will work in humans. Countless drug trials for these diseases have failed over the last ten years, even after encouraging results in animal trials, so there is reason to remain cautious. If the drug proves to be safe in humans, there will be important questions to be answered about when it is given - presumably treatment would need to start early in the disease process to prevent neurodegeneration before it becomes disabling. As we've previously discussed, in PD a significant amount of neurodegeneration occurs before the diagnosis is made, suggesting that even at diagnosis may be too late.
Nonetheless, this is the first time an oral treatment has been shown to completely stop neurodegeneration in its tracks and it represents an important step forward in the search for a definitive treatment for both Parkinson's disease and Alzheimer's disease.
- Anna and Joe
Jargon buster:
Prion diseases are a group of rare progressive neurodegenerative disorders caused by abnormal, misfolded proteins called prions. They are transmissable (can be spread from person to person), but most cases are sporadic.
Translation is the stage of protein production in which single amino acids are put together to form a polypeptide (protein).
Hyperglycaemia: high blood sugar levels (which is what occurs in diabetes).
____
Hoozemans JJ, van Haastert Es, Nijholt DA, et al. Activation of the unfolded protein response in Parkinson's disease. Biochem. Biophys. Res. Commun. 354, 707-711 (2007)
Olanow CW, Brundin P. Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder? Mov. Disord. 28(1), 31-40 (2013)
Moreno JA, Radford H, Peretti D, Steinert JR, Verity, N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori C, Barrett A, Tsaytler P, Bertolotti A, Willis AE, Bushell M, Malluci GR, Sustained translational repression by eIF2a-P mediates prion neurodegeneration. Nature 485, 507-511 (2012)
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