ARTICLE IN BRIEF
Investigators provided early evidence that a small-molecule inhibitor of the PERK (PKR-like endoplasmic reticulum kinase) pathway, a key signaling factor in the unfolded protein response, can restore synaptic protein levels and reduce neurodegeneration in prion-infected mice.
In a May 2012 paper in Nature, investigators reported that dysregulation of correct protein folding could play a key role in a number of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease, with synaptic failure and neuronal loss occurring as a result of changes in the expression of synaptic proteins.
Now, with an Oct. 9 paper in Science Translational Medicine, the same team of authors provides early evidence that a small-molecule inhibitor of the PERK (PKR-like endoplasmic reticulum kinase) pathway, a key signaling factor in the unfolded protein response, can restore synaptic protein levels and reduce neurodegeneration in prion-infected mice.
The researchers, led by Giovanna Mallucci, MD, PhD, professor in the Medical Research Toxicology Unit at the University of Leicester in the UK, fed the oral PERK inhibitor to groups of tg37 transgenic mice infected with the Rocky Mountain Laboratory prion strain, at different stages in the course of their disease. One group received the inhibitor seven weeks after inoculation; the second group received it at nine weeks. (Control mice were infected and treated with vehicle alone at seven and nine weeks, while another control group received the compound without infection.)
Mice treated with the inhibitor at seven weeks did not lose object recognition memory as did other infected mice. The mice that didn't receive the inhibitor until nine weeks, however, had no restoration of their object recognition memory. When administered at seven weeks, the inhibitor also prevented a decline in burrowing behavior seen in early prion disease in mice, and reversed these declines when administered at nine weeks. These clinical findings were confirmed on pathology.
“In both groups of treated animals, the neuronal ribbon of hippocampal regions CA1–4 was protected and did not degenerate, as was observed in vehicle-treated animals by 12 weeks after inoculation,” the authors wrote. Minimal spongiform degeneration and astrocytosis were also observed in the brains of the treated animals.
The popular press seized on these findings, with the BBC hailing them as an “Alzheimer's breakthrough.” It wasn't just the media: Roger Morris, professor of molecular neurobiology at King's College London, told the BBC: “This finding, I suspect, will be judged by history as a turning point in the search for medicines to control and prevent Alzheimer's disease.”
Other neuroscientists have been more cautious.
It's an intriguing finding, to be sure, said Thomas Wisniewski, MD, director of the Memory and Dementia Disorders Center and chief of the Division of Aging and Dementia at New York University Langone Medical Center in New York. “To be able to therapeutically modulate something that's involved in the unfolded protein response is very important, given the involvement of protein folding in most neurodegenerative diseases. Having a means of manipulating this pathway is really significant.”
But, he cautioned that moving forward therapeutically will be extremely tricky given the importance of the PERK pathway. “This is a very important cellular response, and the modification of it can have many off-target [adverse] effects,” he said, noting that Dr. Mallucci and colleagues could not follow survival of the treated animals fully because they were losing weight and had hyperglycemia. “It's certainly something that, with fine-tuning, one could imagine might lead to therapies that would not have these significant [toxic] responses.” But how that would be done, he noted, is “the billion-dollar question.”
With an entity as deadly and fast-moving as prion disease, of course, some adverse effects may be much more acceptable. “Diabetes, for example, is a big concern in the animals who've gotten these PERK agents,” noted Michael Geschwind, MD, the Michael J. Homer chair in neurology at the University of California, San Francisco School of Medicine and an expert in rapidly progressive dementias such as prion disease. “But if you're causing diabetes, maybe that's not the worst thing in a patient who has prion disease. That's something we could probably deal with. With prion disease, even if you could just give the patient a year or even a couple of months, that would be fantastic. But in something like Alzheimer's or Parkinson's, the [adverse] effects are more significant, because the patients are going to live longer and the disease course is longer.”
What's more, the off-target effects may themselves contribute to neurological problems. Diabetes has been observed to exacerbate neurodegenerative diseases as a result of vascular impairment.
Dr. Geschwind also pointed to limitations in the study's findings, particularly the lack of survival data. “They show all these positive behavioral effects, some of which they can ameliorate when there are earlier signs of the disease but not later,” he said. “And there was clearly delayed pathology in the treated mice. But it seems that they sacrificed the mice all at the same time. If we don't know whether or not they improved survival, that's a big question.”
Another caveat, Dr. Geschwind noted, is the mouse model involved. The tg37 mouse has a threefold overexpression of the PrP (prion protein), which translates into a very rapid disease process. Would similar effects be seen in different transgenic mouse models?
“Many times, medications have had very positive effects in prion mouse models but only in one background of mouse,” he says. “When labs try the same drug in another mouse they often find they don't get the same response.”
Despite these limitations, Dr. Geschwind said, the paper is exciting. “It gives us certainly a gleam of hope. I think the next steps include looking at another mouse model, looking to see if the agent can improve survival, and research to determine if they can control the off-target effects.”
Dr. Wisniewski agrees. “Working out the pathways that are involved here and having a means of manipulating them is so important for gaining a better understanding of what's happening in different neurodegenerative diseases, where this unfolded protein response is so critical to the pathogenesis. I see a lot of spin-off research, trying this in other animal models and trying analogous approaches that might be more specific.”
LINK UP FOR MORE INFORMATION:
•. Moreno JA, Radford H, Peretti D, et al. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature
•. Moreno JA, Halliday M, Molloy C, et al. Oral treatment targeting the unfolded protein response prevents prion neurodegeneration and clinical disease in mice. Sci. Transl. Med
2013; 5: 206ra138.
•. Neurology Today
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