Cells grown in the laboratory: In the nucleus (blue), the protein FE65 has fused with other proteins such as BLM to form spherical structures (yellow); © RUB/Thorsten Müller
A new hypothesis has been developed by researchers from the Ruhr-Universität Bochum (RUB) on how Alzheimer's disease could occur. They analyzed the interaction of the proteins FE65 and BLM that regulate cell division.
In the cell culture model, they discovered spherical structures in the nucleus that contained FE65 and BLM. The interaction of the proteins triggered a wrong signal for cell division. This may explain the degeneration and death of nerve cells in Alzheimer's patients. The so-called amyloid precursor protein APP is central to Alzheimer's disease. It spans the cell membrane, and its cleavage products are linked to protein deposits that form in Alzheimer patients outside the nerve cells. APP anchors the protein FE65 to the membrane, which was the focus of the current study.
FE65 can migrate into the nucleus, where it plays a role in DNA replication and repair. Based on cells grown in the laboratory, the team led by Doctor Müller from the Department of Functional Proteomics at the RUB established that FE65 can unite with other proteins in the cell nucleus to form spherical structures, so-called "nuclear spheres". Video microscopy showed that these ring-like structures merge with each other and can thus grow.
Müller's team took a closer look at the function of FE65. By means of genetic manipulation, the researchers generated cell cultures, in which the FE65-production was reduced. A smaller amount of FE65 thus generated a smaller amount of the protein BLM in the nucleus. Instead, BLM collected in another area of the cell, the endoplasmic reticulum. In addition, the researchers found a lower rate of DNA replication in the genetically modified cells. In this way, FE65 influences the replication of the genetic material via the BLM protein. When the researchers cranked up the FE65-production again, the amount of BLM in the nucleus also increased again.
In patients with Alzheimer's disease, the protein APP, an interaction partner of FE65, changes. The interaction of the two molecules is important for the transport of FE65 into the nucleus, where it regulates cell division in combination with BLM. Müller's team assumes that the altered APP-FE65 interaction mistakenly sends the cells the signal to divide. Since nerve cells normally cannot divide, they degenerate instead and die. "This hypothesis, which we pursue in the working group Morbus Alzheimer, also delivers new starting points for potential therapies, which are urgently needed for Alzheimer's disease," says Doctor Mueller. In the future, the team will also investigate whether and how the amount of BLM is altered in Alzheimer's patients compared to healthy subjects.
MEDICA.de; Quelle: Ruhr-Uni Bochum