Although the prospect of a pill for Alzheimer’s remains a long way off, the landmark British study provides a major new pathway for future drug treatments.
The compound works by blocking a faulty signal in brains affected by neurodegenerative diseases, which shuts down the production of essential proteins, leading to brain cells being unprotected and dying off.
It was tested in mice with prion disease – the best animal model of human neurodegenerative disorders – but scientists said they were confident the same principles would apply in a human brain with debilitating brain diseases such as Alzheimer’s or Parkinson’s.
“It’s a real step forward,” team leader Professor Giovanna Mallucci told The Independent. “It’s the first time a substance has been given to mice that prevents brain disease. The fact that this is a compound that can be given orally, that gets into the brain and prevents brain disease, is a first in itself… We can go forward and develop better molecules and I can’t see why preventing this process should only be restricted to mice. I think this probably will translate into other mammalian brains.”
Although the compound also produced significant side effects in mice, including weight loss and mild diabetes, which was caused by damage to the pancreas, Professor Mallucci said it would “not be impossible” to develop a drug that protected the brain without the side effects and that work towards doing so had been “very promising”.
SOURCES- Independent UK, Science Translational Medicine
During prion disease, an increase in misfolded prion protein (PrP) generated by prion replication leads to sustained overactivation of the branch of the unfolded protein response (UPR) that controls the initiation of protein synthesis. This results in persistent repression of translation, resulting in the loss of critical proteins that leads to synaptic failure and neuronal death. We have previously reported that localized genetic manipulation of this pathway rescues shutdown of translation and prevents neurodegeneration in a mouse model of prion disease, suggesting that pharmacological inhibition of this pathway might be of therapeutic benefit. We show that oral treatment with a specific inhibitor of the kinase PERK (protein kinase RNA–like endoplasmic reticulum kinase), a key mediator of this UPR pathway, prevented UPR-mediated translational repression and abrogated development of clinical prion disease in mice, with neuroprotection observed throughout the mouse brain. This was the case for animals treated both at the preclinical stage and also later in disease when behavioral signs had emerged. Critically, the compound acts downstream and independently of the primary pathogenic process of prion replication and is effective despite continuing accumulation of misfolded PrP. These data suggest that PERK, and other members of this pathway, may be new therapeutic targets for developing drugs against prion disease or other neurodegenerative diseases where the UPR has been implicated.
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