Looking at the nucleus of cells to understand Alzheimer’s disease. A group of Italian scientists coordinated by Giannino Del Sal has identified a protein, PIN1, which protects the cell nucleus from malformations. The findings have just been published in Cell Reports.
When the PIN1 protein is absent or present in only small amounts, as happens in the neurons of patients affected by Alzheimer’s disease, DNA loses its order, molecules are produced that trigger inflammation and the cells degenerate. The discovery was made by a group of scientists coordinated by Giannino Del Sal, Professor at the University of Trieste, Researcher at IFOM Milan, and Group Leader at ICGEB. The study was also undertaken in collaboration with scientists at SISSA.
The cells of our tissues are subjected to stimuli and stress of different nature to which they respond by modifying and regulating the organisation of the genome and the expression of genes. A crucial mechanism underlying this ability pivots on the PIN1 protein, involved in the decoding of different types of signals that the cell receives, and is therefore implicated in multiple pathophysiological processes. Alterations in its levels are associated with different disease conditions: an increase in PIN1 contributes to the formation of tumours and metastases, while its decrease is observed in neurodegenerative diseases such as Alzheimer’s dementia.
Until now, little was known about the molecular mechanisms that in the absence, or with reduced levels, of PIN1, lead to cellular degeneration. The results of the study, published in Cell Reports, reveal that PIN1 functions as a guardian of the cell nucleus, preserving its structure and protecting the DNA contained in it from stress of a mechanical nature. Cells are increasingly subjected to stress during aging. The study shows that PIN1 regulates the function of proteins important for preserving the structure of the nucleus and the organisation and anchorage of the genome within. This control allows the nucleus to withstand mechanical stress without altering DNA organisation and gene regulation. During aging, other dysfunctions can lead to significant reductions in PIN1 levels. In neurons, this, in turn, causes malformations of the nucleus, disorganisation of the genome, DNA damage, and production of molecules that trigger inflammatory reactions. These, in turn, and ultimately, lead nerve cells to degeneration.
“Several alterations in the organisation of the genome and in the activity of genes are associated with aging and can lead to DNA damage and inflammation, contributing to cell degeneration” explains Giannino Del Sal, Director of the Laboratory of “Cancer Cell Signalling” at the ICGEB in Trieste, Professor of the University of Trieste, and head of the research program “Signaling, tumour microenvironment and cellular metabolism” at IFOM Milan.
“This study,” says Del Sal, “has led to the identification of proteins whose function can be pharmacologically modulated to prevent or improve the course of aging diseases such as Alzheimer’s. The goal is now to develop molecules that promote its protective function against the cell nucleus and verify its effect in preclinical models of the disease…We are actively conducting our research also to better understand the role of PIN1 and the mechanism we have discovered in this context, and the way in which we can exploit it to our advantage to develop new therapeutic strategies”.
Link to Paper: Napoletano, F., Ferrari Bravo, G., Voto, I.A.P., Santin, S., Celora, L., Campaner, E., Dezi, C., Bertossi, A., Valentino, E., Santorsola, M., Rustighi, A., Fajner, V., Maspero, E., Ansaloni, F., Cancila, V., Valenti, C.F., Santo, M., Artimagnella, O.B., Finaurini, S., Gioia, U., Polo, S., Sanges, R., Tripodo, C., Mallamaci, A., Gustincich, S., d’Adda di Fagagna, F., Mantovani, F., Specchia, V., Del Sal, G. 2021. The prolyl-isomerase PIN1 is essential for nuclear Lamin-B structure and function and protects heterochromatin under mechanical stress. Cell Reports 36, 109694