Universit� degli studi di Modena e Reggio Emilia

A study by Prof. Serena Carra of Unimore has found the anti-stress recipe for the TDP-43 proteins linked to ALS diagnosis

When proteins become stressed, they lose their capacity and cells reduce their functionality. In this case, reference is made 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 protective mechanism, SUMOylation, that prevents the aggregation of TDP-43.

In a study recently published in the prestigious Science Advances , Prof. Serena Carra and the research team at the University of Modena and Reggio Emilia have found the mechanism that activates SUMOylation of TDP-43 and, as a result, laid concrete foundations for studying new therapeutic targets in the near future.

How the TDP-43 works

The TDP-43 protein binds numerous RNAs and regulates their functionality. On the other hand, RNA stabilises the TDP-43 protein and prevents its aggregation, which causes loss of function. However, under stress conditions, TDP-43 may not bind RNA efficiently and becomes vulnerable, so the cell activates a protective mechanism: SUMOylation, i.e. the cell attaches SUMO tags (particularly SUMO2/3) to the TDP-43 protein. There is a specific enzyme that performs this function, identified by Prof. Carra's research group: it is called PIAS4 and is like a guardian that safeguards the defenceless TDP-43 molecules and through SUMOylation maintains their solubility in dangerous conditions.

In individuals with sporadic and familial forms of ALS and Frontotemporal Dementia, the PIAS4 guardian 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 per cent of Alzheimer's patients with TDP-43 aggregates. 

Serena Carra, Associate Professor of the Department of Biomedical, Metabolic and Neuroscience at Unimore: "The main functions of TDP-43, its presence in aggregates in the cells of ALS and Frontotemporal Dementia patients, as well as the detrimental effects of its aggregation have been known for about 20 years. However, no one had fully understood the importance of the mechanism of SUMOylation and its protective role for the TDP-43 protein.  In 2019, we realised that this mechanism had been carelessly neglected and opened a new line of research. Today, we have shown that SUMOylation keeps the TDP-43 protein stable and manages to prevent its aggregation under stress conditions, maintaining its functionality necessary for cellular life. This protective mechanism does not affect all TDP-43 molecules, but only those that, due to stress, are in a dangerous situation and do not efficiently bind RNA, its “life partner”. Future studies will have to establish whether new pharmacological approaches aimed at enhancing the activity of TDP-43's guardian, PIAS4, and this protective mechanism, SUMOylation, can counteract TDP-43 aggregation in ALS and Frontotemporal Dementia patients."

Serena Carra was able to conduct research into the molecular mechanisms involved in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia thanks to the contribution of three organisations committed to supporting research: the mid-career Grant financed by the Armenise Harvard Foundation and Airalzh Onlus in 2022-23, reserved for researchers who have reached the midpoint of their career with the aim of pursuing research at a critical stage of their professional career, and several Grants supported since 2014 by the AriSLA Foundation, through its annual Calls for Proposals intended to finance innovative ALS research projects, selected after a rigorous scientific evaluation. 

“Doing good research and obtaining solid and concrete results requires dedication, critical spirit, and far-sightedness’.  - continues Serena Carra - "The results of this study start from an intuition born more than 5 years ago, but the ability to recognise its importance is based on experience. It is only thanks to many years of studying the quality control mechanisms of neuronal cells and how they respond to stress conditions that it has been 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." 

Serena Carra

After more than 10 years of research in Canada and the Netherlands, she returned to Italy thanks to the “Rita Levi Montalcini” Young Researchers Programme.  In her laboratory, she does research in the field of neurodegenerative diseases, in particular Amyotrophic Lateral Sclerosis, and her findings have inspired new research at an international level.

Prof. Carra's studies focus on understanding the role of molecular chaperones and protein quality control systems in maintaining the dynamic properties of biomolecular condensates, the conversion of which into an aggregated state is associated with numerous neurodegenerative diseases.

Prof. Serena Carra has to her credit more than 90 printed publications in journals of international scientific prestige and has obtained funding from prestigious national and international agencies, such as the European Union, MUR, Telethon Foundation, AriSLA Foundation, Cariplo Foundation, Association française contre les myopathies, Agenzia Italiana del Farmaco, Ministry of Health and Ministry of Foreign Affairs and International Cooperation, and Muscular Dystrophy Association Americana. Professor Serena Carra was awarded the Ferruccio Ritossa Early Career Award by the Cell Stress Society International in 2017 and the Mid-Career Award in Neurodegenerative Diseases by the Armenise-Harvard Foundation and AirAlzh in 2022.

Armenise Harvard Foundation

The Giovanni Armenise Harvard Foundation was set up with the aim of supporting basic research in the biomedical field. It helps young scientists working abroad to establish their laboratory in Italy and supports various research programmes at Harvard Medical School in Boston. It has invested over $70 million at Harvard and $39 million in Italian science, creating many research programmes and fostering collaboration between the two continents.

The Career Development Award (CDA) funding amounts to $200,000 per year (for a period of between three and five years. To date, the CDA programme has supported 33 young scientists.

The CDAs have established laboratories in Milan (EIO, IFOM/FIRC, San Raffaele Institute, University of Milan, CNR), Rome (La Sapienza, EBRI), Padua (VIMM, University of Padua), Trento (CIBIO Department, University of Trento), Palermo (University of Palermo), Trieste (SISSA), Pavia (University of Pavia), Pozzuoli (Tigem), Turin (Italian Institute of Genetic Medicine, University of Turin), Rovereto (IIT), and Camerino (University of Camerino), Genoa (IIT).

Fields covered include neuroscience, plant biology, biochemistry, immunology, cancer biology, proteomics and genetics, synthetic biology and stem cells.

Airalzh (Italian Alzheimer Research Association)

Airalzh (“Italian Alzheimer Research Association”) is the only association that promotes medical and scientific research on Alzheimer's disease and other forms of dementia on a national scale. It was set up in 2014 by clinicians and university researchers, who have been involved in the study and treatment of the disease for years, and corporate managers. From 2016 to 2020, the Association has provided 82 research grants (both basic and clinical), for an investment of EUR 2 million, thanks to the support of large and small donors. It has involved 33 young researchers - working in the best universities and research centres located in 15 Italian regions, between North and South - who have obtained more than 250 publications in international journals. Since 2020, the AGYR (Airalzh Grants for Young Researchers) call for proposals has been published annually, with an annual investment of €300,000. To date, 32 projects have been selected, with a total investment of €1,500,000. A new Call for Proposals (AGYR 2025) is about to be issued next spring. In addition to these are the investments for the AHA-MCA calls. Finally, selected projects from the Starting Grants and Art-therapy 2024 will be released shortly.

AriSLA - Italian Research Foundation for Amyotrophic Lateral Sclerosis

Established in 2008 to promote, finance and coordinate scientific research of excellence on ALS in Italy, Fondazione AriSLA is the main organisation at Italian level and in the European panorama to deal exclusively with ALS research. It was set up by the will of four subjects of excellence in the scientific and philanthropic field, such as AISLA Aps, Fondazione Cariplo, Fondazione Telethon ETS and Fondazione Vialli e Mauro per la Ricerca e lo Sport Onlus. To date, it has invested EUR 17 million in research, supported 160 researchers and 115 projects, which have generated over 400 scientific publications.

Categorie: International - english, Notizie_eng