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Could therapeutic small molecules help nerve cells overcome the effects of misfolded proteins during Alzheimer’s?
Claudia Duran-Aniotz
Instituto de Neurociencia Biomedica (BNI)
Santiago, Chile
Background
In healthy cells, a structure called the endoplasmic reticulum (ER) helps make and fold proteins correctly. Unfortunately, this structure is drastically altered during normal aging and in Alzheimer’s, resulting in cells that are less able to repair misfolded and damaged proteins. These misfolded and damaged proteins build up and stress the cells; this leads to nerve cell damage.
Protein-folding is monitored in the ER by a biological process called the unfolded protein response (UPR). This process is activated by proteins on the surface of the ER that act as sensors of misfolded proteins. One of the UPR sensor proteins, (called inositol-requiring enzyme 1 (IRE1)) in turn activates the UPR to help correct folding processes. However, continuous activation of the sensor protein, which may occur during Alzheimer’s, leads to cell death.
Research Plan
Dr. Claudia Duran-Aniotz and colleagues will test the therapeutic benefits of administering two novel chemical compounds to block IRE1 activity in genetically-engineered Alzheimer’s-like mice. The researchers will determine if these compounds can prevent overactivation of IRE1 that may avoid nerve cell death and preserve learning and memory functions in the mice. Dr. Duran-Aniotz will also measure if the inhibitors have any effect on harmful beta-amyloid levels, a protein that is often misfolded during Alzheimer’s. Finally, Dr. Duran-Aniotz will determine if these compounds affect levels of other biological markers of stress in different regions of the mouse brains.
Impact
The results of this study could represent the first important steps toward new avenues of therapy development to help nerve cells survive in the presence of misfolded proteins, such as beta-amyloid and tau protein that are hallmarks of Alzheimer’s. It may also provide new insights into how the UPR could be manipulated to help protect nerve cells stressed by aging and neurodegenerative disorders.
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