We’ve had quite a few articles about dementia research lately — here, here and here — because so many new findings are being announced. Scientists are discovering more about what actually causes dementia, as well as factors that might reduce it or lead to better treatment.
Here’s the latest exciting example, reported by Newsweek, which could completely transform how dementia is treated. It starts with a new understanding of what is happening at the cellular level.
The established wisdom, not just for dementia and Alzheimer’s but for other neurodegenerative diseases like Parkinson’s, is that the root cause is the build-up of abnormal clumps of protein around the brain. The article quotes Michael Rapé, professor of cell and developmental biology at UC Berkeley: “We always thought that protein clumps directly kill neurons, for example by puncturing membrane structures within these cells.”
The logical treatment would be to break up these “abnormal clumps.” Unfortunately, that approach has shown little success. But what if something else is going on?
New research from Rapé’s lab “suggests that these protein accumulations may not actually be responsible for killing our brain cells. Rather, it appears the brain cells are dying due to the body’s own failure to turn off their stress response.” In other words, the cells mount a stress response to cope with the bad proteins, but then the response mechanism stays on, and it is that failure to “turn off” the stress response that actually kills the cells.
From the article: “Rapé compared this to cleaning up your room before turning your light off when going to bed—if you don’t turn off the light, you can’t fall asleep. But if you turn off the light before you clean up your room, you would stumble in the dark over your messy floor. ‘Aggregates don’t kill cells directly,’ he said. ‘They kill cells because they keep the light on. But that means that you can treat these diseases …You treat them with an inhibitor that turns off the light. You don’t have to worry about completely getting rid of large aggregates, which changes how we think about treating neurodegenerative diseases. And most importantly, it makes this really doable.'”
His team discovered a large protein complex which they named SIFI (Silencing Factor of the Integrated stress response), a molecular machine that “first cleans up the abnormal protein clumps and, when it’s done, switches of the brain cells’ stress response, mounted to cope with the abnormal proteins.” Turning off that stress response-silencing mechanism is the key:
“[Protein] aggregates kind of hijack that natural stress response-silencing mechanism, interfere with it, stall it,” Rapé said. “And so that’s why silencing never happens when you have aggregates, and that’s why cells die.”
Future treatments would therefore focus on turning off the stress-response and reactivating the SIFI complex to clear up any built-up proteins.
What’s particularly exciting here is how far scientists are able to penetrate into what is happening at the cellular level, and the interplay between the body’s own mechanisms for dealing with invaders and the way those invaders inhibit those mechanisms. That understanding could unlock more successful treatments — and we’ll certainly report on them as they emerge.