In what could be a breakthrough for Alzheimer's and Parkinson's research, U.K. scientists have prevented neurodegeneration in mice using an existing compound to block a pathway associated with brain cell death.
Last year, researchers at the Medical Research Council Toxicology Unit at the University of Leicester identified a major pathway leading to brain cell death in mice. They observed that when misfolded proteins build up in the brains of mice, a natural defense mechanism is triggered in cells, which switches off the production of new proteins. Normally, this mechanism would kick back in again, but as more and more misshapen proteins build up, the mechanism stays off, preventing the formation of new, essential proteins. This eventually leads to brain cell death.
The team initially tried injecting a protein to block the "off" switch of the pathway and was able to restore the making of protein and stop neurodegeneration. From there, scientists theorized that compounds that could block the pathway could also stop neurodegeneration.
Using that research as a starting point, the team used an oral treatment with a specific inhibitor of the kinase PERK (protein kinase RNA–like endoplasmic reticulum kinase)--originally developed by GlaxoSmithKline ($GSK) for a different purpose: to test in mice with prion disease, a condition that mimics human neurodegeneration. The researchers observed that the PERK inhibitor was able to cross the blood-brain barrier and halt the disease throughout the whole brain.
It could be a big step forward for treating neurodegenerative disorders, but despite its protective properties, mice that were given the compound lost 20% of their body weight as a result. The treatment also caused mild diabetes and damage to the pancreas.
"We're still a long way from a usable drug for humans--this compound had serious side effects. But the fact that we have established that this pathway can be manipulated to protect against brain cell loss, first with genetic tools and now with a compound, means that developing drug treatments targeting this pathway for prion and other neurodegenerative diseases is now a real possibility," said Leicester University professor Giovanna Mallucci, who led the study.
The findings were published in Science Translational Medicine.
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- check out the study abstract