Not All Brain Cells Have Equal Functionality

As far as proteins removal goes, some brain cells process proteins several times faster than other brain cells can. 

Proteostasis is a process in which cells break up and get rid of defective proteins. It can be thought of as a recycling process in human cells.

A study focus on Huntington's Disease show that striatal neurons, brain cells that regulate movement, have a slower proteostasis process than other neurons. And slower proteostasis means malfunction proteins are left to remain in these brain cells longer, cause more damage and lead to more cell deaths.

New observations bring scientists to a better understanding why certain nerve cells die in Huntington’s, a genetic brain disorder that leads to uncontrolled movements and death.

The speed at which damaged proteins are cleared from neurons may affect cell survival and may explain why some cells are targeted for death in neurodegenerative disorders.

It helps solve one of the mysteries surrounding neurodegenerative diseases. It is especially puzzling because the protein thought to be responsible for cell death is found throughout the brain in many of these diseases, yet only certain brain areas or cell types are affected.

In Huntington’s disease and many other neurodegenerative disorders, proteins that are misfolded (abnormal shapes), accumulate inside and around neurons and are thought to damage and kill nearby brain cells.

Normally, cells can clear them away before they do any damage. Effective proteostasis control protein levels and quality. Our brains have powerful coping mechanisms to deal with disease-causing proteins. It shows in the fact that some of these diseases don’t show symptoms until the fourth or fifth decade of life, even when the gene has been present since birth, suggests that those mechanisms diminish as we age.

The mutant version of huntingtin repeat an abnormal number of times to cause it to misfold, delay proteostasis, and eventually lead to neuron death and the symptoms of the disease.

The researchers found that the amount of time the mutant protein remained in the cell predicted neuronal survival. To test this idea that improving proteostasis in Huntington’s brains may improve neuronal survival, the researchers activated Nrf2, a protein known to regulate protein processing. When Nrf2 was turned on, the mean lifetime of huntingtin was shortened, and the neuron lived longer.

“Nrf2 seems like a potentially exciting therapeutic target. It is profoundly neuroprotective in our Huntington’s model and it accelerates the clearance of mutant huntingtin,” said Dr. Steven Finkbeiner, senior author of the paper, a research project partially funded by the National Institute of Health.