International Business Department           Liu Bojia           March 06, 2023

  Alzheimer's disease and Parkinson's disease are common neurodegenerative diseases in the elderly population, which are characterised by the decline and gradual death of nerve cells in specific brain regions. Over the years, it has been discovered that nerve cells undergo an abnormal accumulation of proteins before they die. Scientists have hypothesised that tangled protein clumps kill nerve cells, and are hoping to prevent or treat neurodegenerative diseases by removing the disease-causing protein clumps to protect the nerve cells.

  However, this type of therapeutic strategy has not worked as well as expected. Does this mean that there is another culprit killing nerve cells?

  In a new research paper published in Nature, researchers at the University of California, Berkeley (UC Berkeley) propose that it's not the protein aggregates that build up inside the cell that directly kill the neuron, but rather the stress that the cell is under continually. And according to this theory, drugs that help cells turn off the stress response are expected to offer treatment options for a range of neurodegenerative diseases.

  In their paper, the researchers note that the stress response helps cells cope with temporary adverse conditions, such as exposure to toxins, nutritional restrictions or temperature fluctuations. But if stress signals persist - such as aging or disease - indicating that the cell is consistently in unfavourable conditions, cell death can be triggered.

  In this paper, the researchers then found that in some neurodegenerative diseases, abnormal protein aggregates trigger a cellular stress response, but the mechanism that shuts down the cellular stress response is disturbed, and the persistent stress signals lead to cell death.

  Specifically, the cells have a large molecular machine known as the syntrophic stress response silencing factor (referred to as the SIFI complex), which belongs to the ubiquitin E3 ligase. As described by the researchers, SIFI has two main functions: there are aggregated nascent proteins in the wrong place in the cell, which SIFI can degrade; and when removal is complete, SIFI shuts down the cellular stress response triggered by the aggregated proteins.

  In order to achieve these two functions, the core substrate of the SIFI complex has two proteins, one of which monitors the cytoplasm for proteins that have failed to enter the mitochondria correctly by recognising specific motifs, and once recognised it activates the other kinase, which shuts down the process of synthesis of the majority of the new proteins. This process is part of the cellular stress response. Subsequently, when the cell corrects the problem of mislocalised proteins, the kinase is degraded by SIFI and the stress response shuts down.

  When SIFI functions properly, it shuts down the stress response at the right time; but when SIFI malfunctions - for example, when a key SIFI constituent molecule is mutated - protein plaques accumulate in the cell and a sustained stress response occurs. This stress response signalling kills the cell.

  And in this study, the authors of the paper found in models of ataxia and early-onset dementia, two neurodegenerative diseases, that UBR4, a key component of SIFI, was mutated, which prevented the cell's stress response from being terminated.

  Nevertheless, one can use drugs to force the stress response to shut down. In cells with early-onset dementia-specific genes, the researchers attempted to restore the stress-shutdown function of SIFI with an inhibitor and found that it was sufficient to rescue neuronal function and maintain their survival.

  Dr Michael Rapé, corresponding author of the paper, noted that many neurodegenerative diseases occur when abnormal proteins accumulate in specific nerve cells, which may prevent the cells from shutting down the stress response. They found the prolonged stress response in more than a dozen neurodegenerative diseases. They speculate that using drugs to turn off this stress response may save nerve cells and lead to new ways of treating neurodegenerative diseases such as Alzheimer's disease.