Alzheimer's, here are the new proteins that prevent the disease

When proteins are stressed, they lose their capacity and cells reduce their functionality. In this case we are referring to the TDP-43 protein, whose accumulation in the form of aggregates is associated with neuronal death and is a marker of Amyotrophic Lateral Sclerosis (ALS), Alzheimer's, and Frontotemporal Dementia (FTDL). The body, when healthy, has found a protection mechanism, sumoylation, which prevents the aggregation of TDP-43. In a study recently published in Science Advances , Serena Carra, professor of the Department of Biomedical, Metabolic and Neurosciences of Unimore and the research team of the University of Modena and Reggio Emilia, have found the mechanism that activates the sumoylation of TDP-43 and, consequently, have laid concrete foundations for studying, in the near future, new therapeutic targets.

What is TDP-43 protein?

The TDP-43 protein binds numerous RNAs and regulates their functionality. On the other hand, RNA stabilizes the TDP-43 protein and prevents its aggregation, which causes its loss of functionality. However, under stress conditions TDP-43 may not bind RNA efficiently and becomes vulnerable, so the cell activates a protective mechanism: sumoylation, in fact, that is, the cell attacks SUMO tags (in particular SUMO2/3) on the TDP-43 protein.

There is a specific enzyme that performs this function, identified by Professor Carra's research group: it is called PIAS4 and is like a guardian that safeguards the defenseless TDP-43 molecules and through summation maintains their solubility in dangerous conditions.

In people with sporadic and familial forms of ALS and frontotemporal dementia, the PIAS4 gatekeeper fails to protect endangered TDP-43 molecules, and this protective mechanism becomes defective. Future studies will investigate whether this mechanism is also impaired in the 50% of Alzheimer's patients who have TDP-43 aggregates.

Mechanism of sumoylation revealed

For Carra, "the main functions of TDP-43, its presence in aggregates in the cells of patients with ALS and frontotemporal dementia, as well as the harmful effects of its aggregation have been known for about 20 years". And she continues: "However, no one had fully understood the importance of the sumoylation mechanism and its protective role for the TDP-43 protein. In 2019 we realized that this mechanism had been carelessly neglected and we opened a new line of research". The scientist underlines: "Today we have demonstrated that sumoylation keeps the TDP-43 protein stable and is able to prevent its aggregation in conditions of stress, maintaining the functions necessary for cellular life. This protective mechanism does not concern all TDP-43 molecules, but only those that, due to stress, are in a dangerous situation and that do not efficiently bind RNA, its 'life companion'. Future studies will need to establish whether new pharmacological approaches aimed at enhancing the activity of the TDP-43 gatekeeper, PIAS4, and of this protective mechanism, sumylation, will be able to counteract TDP-43 aggregation in patients with ALS and Frontotemporal Dementia”.

The research

Carra was able to conduct research on the molecular mechanisms involved in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia thanks to the contribution of three organizations committed to supporting research: the Mid-Career Grant funded by Fondazione Armenise Harvard and Airalzh Onlus in 2022-23, reserved for researchers who have reached the middle of their career with the aim of continuing their research in a critical phase of their professional path, and several Grants supported since 2014 by Fondazione AriSLA, through its annual calls for proposals aimed at financing innovative research projects on ALS, selected after a rigorous scientific evaluation.

"To do good research and obtain solid and concrete results, dedication, critical thinking, and foresight are needed - concludes Carra -. The results of this study start from an intuition born more than 5 years ago, but the ability to recognize its importance is based on experience. It is only thanks to many years of study on the mechanisms of quality control of neuronal cells and on how they respond to stress conditions that it was possible to transform an intuition into a scientific result that helps us better understand why TDP-43 aggregates and on which we can design new pharmacological approaches".