Mice with a form of dementia have had the condition reversed by a process that involves ‘rebooting’ brain cells otherwise destined to die.
The process that kills the cells could be common to all dementias, so blocking it in the same way might hold promise for Alzheimer’s disease and Parkinson’s disease – although more research is needed to explore this further.
“This is potentially a common pathway in all these diseases,” says Giovanna Mallucci at the University of Leicester, UK. “The key thing is that we’ve moved away from a disease-specific mechanism to a more generic cause of cell death,” she says.
Mallucci and colleagues treated mice that were bred to develop a form of prion disease similar to mad cow disease and Creutzfeldt-Jakob disease. Misfolded prion proteins accumulate in cells, forming dense plaques that clog up the brain and kill brain cells in the process.
Instead of trying to tackle the prions or plaques – an approach that has so far proved unsuccessful in Alzheimer’s disease – Mallucci’s team tackled another process that goes wrong in the affected brain cells: a complete shutdown of protein production.
Such shutdowns are routine in healthy cells if they produce too many misfolded or unfolded proteins, but normal protein production resumes again once the mess is sorted out.
In prion diseases, and possibly in other dementias blighted by the accumulation of plaques, normal protein production is shut down permanently. This kills neurons and destroys their connections to neighbouring cells.
In the mice with prion disease, Mallucci disrupted this process by neutralising the gene – called eukaryotic translation initiation factor, or eIF2alpha-P – that halts protein production. Called eukaryotic translation initiation factor, or eIF2alpha-P, the gene generates a protein that needs to have a chemical grouping called a phosphate group attached to it to halt the protein production line.
Mallucci’s team restarted protein production with a treatment that stripped off the phosphate group. They did this by using a virus to load into the mice’s brains extra amounts of another protein, called GADD34, which snips off the crucial phosphate from the eIF2alpha-P protein.
By rebooting protein production, the treatment halted any further degeneration in the mice. Post mortems showed that brain connections lost in the untreated mice remained healthy, and completely normal protein production had resumed in the treated animals, even though the prions continued to accumulate. The treatment slightly extended the lifespan of the treated mice too. On average they died after 90 days. Untreated mice died after 83 days on average.
“We think it worked because we hit the executioner of the cells,” says Mallucci. One challenge now, she says, is to find drugs that reboot normal protein production in the same way. A second challenge is to see if the same “production line closures” are what kill cells in patients with Alzheimer’s and other dementias. If they are, then finding a drug to halt them might work in several diseases.
Mallucci says that there is hope, because the eIF2alpha-P protein is already known to be produced in abnormally high amounts in Alzheimer’s, which suggests that it is potentially blocking protein production in the same way as in prion diseases.
“The burning question posed by this work is whether similar mechanisms operate in more common neurodegenerative diseases characterised by pathological protein deposits, including Alzheimer’s, Parkinson’s and Huntington’s disease,” says Andy Randall at the University of Bristol, UK.