Leah Stamm

Written By Leah Stamm

Based on the research done at Micheal Rapé’s Lab at UC Berkeley: Stress response silencing by an E3 ligase mutated in neurodegeneration (Nature)

About

Degenerative diseases like Alzheimer’s or Parkinson’s are often characterized by the buildup of toxic proteins in the brain. A common analogy refers to your brain as a city; the neural pathways as a subway system; the proteins as the commuters on the train. In this scenario, neurodegenerative diseases are explained as some of the proteins going rogue to form toxic clusters—like a traffic jam—that disrupt the normal functioning of brain cells.

The understanding in the scientific community had been that these protein aggregates were the cause of neurodegenerative diseases. Much of the current research has focused on depleting these clusters to prevent disease progression. However, a groundbreaking discovery from researchers at Micheal Rape’s lab at UC Berkeley challenge this long-held belief.

Findings

What they found was surprising: it’s not solely the aggregates causing harm to the brain; rather, it's the brain’s response—or lack thereof—to these aggregates that contributes to the damage.

Consider: when you encounter a stressful situation, your sympathetic nervous system—the fight, flight, or freeze response—is activated. Your heart races, your blood pressure soars, your pupils dilate. Under normal circumstances, the automaticity of this stress response is helpful: it forces you to act before your mind has time to make a conscious decision. However, existing in this heightened state for prolonged periods of time can be damaging. Ideally, once the situation that elicited the stress response—the emergency, the race, the scary movie— ends, the body must come back to homeostasis, to neutral. However, too much time under the stress response can cause anxiety attacks, hyperventilation, or possibly PTSD.

Similar to the body, the brain has its own stress response mechanisms. Whether it's battling a common cold or facing a more serious threat like potential tumor growth, the brain has intricate pathways to detect and mitigate stress, aiming to maintain the delicate balance of cellular and tissue health.

If functioning properly, the brain will turn on the stress response when it notices the formation of these protein aggregates and take to cleaning up its subway system. Once everything is tidy, the stress response turns off and functioning goes back to normal.

However, what happens when the stress signals in the brain never turn off? Well, it tells the body that the cell cannot be fixed: it is irreversibly damaged and must be eliminated entirely. For example, this could be true of a tumorigenic cell. So the brain triggers apoptosis, the process of programmed cell death, to eliminate the cells in question.

It’s a necessary process when dealing with actual threats. However, when these signals become chronic and unwarranted, they can lead to the premature demise of healthy brain cells.

Rapé explains this finding in simple metaphorical terms:

“You not only need to clean up your room, but also turn out the light before going to bed. If you don’t turn off the light, you can’t fall asleep, but if you turn it off before you clean up your room, you would stumble if you had to get up in the dark. Similarly, a cell has to clean up protein aggregates before turning off the stress response. If it doesn’t turn off the stress response, the cell will ultimately die. Aggregates don't kill cells directly. They kill cells because they keep the light on,” (Berkeley News).

Impact

In essence, the research done by Rape’s Lab prompts us to reconsider our understanding of neurodegenerative diseases. It’s not just about targeting the aggregates; it's about deciphering how the brain responds to them. By unraveling this complex relationship, we may uncover new avenues for therapeutic intervention, potentially shifting the paradigm in our approach to these debilitating diseases.

Related Information

Michael Rapé Lab Home Page
Original Article in Nature Academic Journal: Stress response silencing by an E3 ligase mutated in neurodegeneration (Nature)
Berkeley News Article by Robert Sanders: Are stressed-out brain cells the root cause of neurodegenerative disease?