Nuak1. It sounds like it could be the name of an android or a distant moon in an upcoming sci-fi film. It is, in fact, an enzyme that recent research shows plays a key role in creating a protein in the brain that contributes to Alzheimer's disease. Manipulating Nuak1 to our advantage could eventually make treating the condition akin to fighting cholesterol with statins, say scientists.
In a study published in the journal Neuron, researchers describe how they turned their attention to a protein called tau that becomes toxic to the brain when it builds up in excessive quantities, and has been linked to Alzheimer's and dementia. Limiting tau, they reasoned, might just limit the neurodegeneration that occurs with the diseases. And one way to limit tau is to find the enzyme that helps cells produce it.
They hunted for the right compound by inhibiting 600 different enzymes called kinases in human cells and in fruit flies. They found that when they inhibited Nuak1, the levels of tau dropped.
Build-up of the protein known as tau forms tangles in brain tissue seen as the dark spots on the left, but cutting the enzyme that produces it – Nuak1 – by 50 percent leads to far fewer tangles (right side)
"Screening hundreds of kinases in the fruit fly animal model was critical because we could assess degeneration caused by tau in the fly's nervous system and measure neuronal dysfunction," said co-senior author Dr. Juan Botas, professor of molecular and human genetics and of molecular and cellular biology at Baylor College of Medicine. "Screening such a large number cannot be done with other animal models like the mouse, and cultured cells cannot model complex nervous system functions."
Speaking of mice however, the research team's next step was to see if their discovery would hold in tests using the rodents. It did. "Inhibiting Nuak1 improved the behavior of the mice and prevented brain degeneration," said senior author Huda Zoghbi, a professor at Baylor and director of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.
Because the researchers had positive results across three systems – human cells, fruit fly and mouse – they feel hopeful that drug treatment based on Nuak1 could help battle Alzheimer's and other types of dementia. In fact, says Zoghbi, the treatment could one day be as simple as taking a statin to fight high cholesterol is today.
"When people started taking drugs that lower cholesterol, they lived longer and healthier lives rather than dying earlier of heart disease," she said. "Nobody has thought about Alzheimer's disease in that light.
"Tau in Alzheimer's can be compared to cholesterol in heart disease. Tau is a protein that when it accumulates as the person ages, increases the vulnerability of the brain to developing Alzheimer's. So maybe if we can find drugs that can keep tau at levels that are not toxic for the brain, then we would be able to prevent or delay the development of Alzheimer's and other diseases caused in part by toxic tau accumulation."
You can hear more from Zoghbi in the video below.
Source: Baylor College of Medicine