UC Berkeley Study Finds Stress Response, Not Protein Aggregates, Kills Brain Cells
Research into neurodegenerative diseases like Alzheimer’s and Parkinson’s has taken a new turn. While these conditions have been associated with the accumulation of protein aggregates in the brain, a team from the University of California, Berkeley has discovered that the real culprit behind brain cell death is the failure to deactivate the cells' stress response.
In findings published in Nature, researchers reveal that a drug designed to halt the stress response can rescue cells modeled after a type of neurodegenerative disease known as early-onset dementia.
The Crucial Role of the SIFI Complex in Neurodegeneration
Lead researcher Michael Rapé highlights the potential of this discovery in providing new treatment avenues for neurodegenerative diseases, especially those resulting from mutations in the protein responsible for switching off the cellular stress response. Conditions such as ataxia and early-onset dementia could benefit from this innovative approach.
Rapé further explains that other neurodegenerative disorders, including Mohr–Tranebjærg syndrome and Leigh syndrome, also exhibit uncontrolled stress responses, presenting symptoms akin to the early onset dementia explored in their study.
"It was previously believed that protein clumps directly caused neuron death, possibly by damaging internal cell structures. However, our research indicates that these aggregates actually prevent the cessation of a stress response initially meant to manage these defective proteins. This perpetual stress state leads to cell death," Rapé elucidates. "We suspect similar mechanisms may be at play in more prevalent conditions characterized by protein aggregation, such as Alzheimer’s disease or frontotemporal dementia, although further research is needed."
Rapé's lab made a key discovery that stress responses must be terminated once a cell overcomes a challenging situation. He simplifies this concept: "You need to not only clean your room but also turn off the light before sleeping. Leaving the light on prevents sleep, but turning it off too early could lead to stumbling in the dark."
Accordingly, a cell must first address protein aggregates before deactivating the stress response. Failure to do so results in cell death.
"The presence of aggregates doesn’t directly lead to cell mortality. They cause death by keeping the stress response active," he notes. "However, this understanding opens up treatment possibilities for neurodegenerative diseases, specifically those where the stress response remains unchecked. Targeting the disease with an inhibitor that 'turns off the light' shifts our perspective on neurodegenerative disease treatment and presents a viable approach."
The paper details a newly identified protein complex named SIFI (Silencing Factor of the Integrated stress response), which not only helps clear protein aggregates but also deactivates the stress response afterwards. If SIFI components are mutated, cells accumulate protein clumps and experience an ongoing stress response, ultimately leading to cell death.
"Normally, SIFI would eliminate aggregating proteins. When aggregates are present, SIFI's attention is diverted from the stress response, allowing the signaling to persist. Once the aggregates are cleared, SIFI can resume its function and turn off the stress response," Rapé explains. "Aggregates essentially hijack and stall this natural mechanism, preventing the silencing of the stress response and leading to cell death."
Future treatments could involve administering a drug to deactivate the stress response and another to maintain SIFI's activity in clearing the aggregates.