Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), Huntington’s disease, frontotemporal dementia (the disease that struck the actor Bruce Willis): different pathologies, which have in common the fact that they depend on the accumulation of protein aggregates. That is, proteins that lose their three-dimensional structure and end up aggregating with each other or with other components of the cellular matrix, completely losing their functionality or even becoming toxic for the cell and understanding the mechanisms underlying this process in ever greater detail could lead to new treatments in the future.
And exactly this is what Serena Carra deals with, having returned to Italy after more than 10 years of activity in Canada and Holland, and whose discoveries have inspired new research at an international level. She is now an associate professor at the University of Modena and Reggio Emilia and has won two awards that allow her to carry on the studies of her laboratory: a grant from the Telethon Foundation for rare diseases and the first mid-career award from Airalzh airalzh.it and Armenise-Harvard Foundation armeniseharvard.orga unique recognition of its kind dedicated to “mid-career” researchers, whose new call opens today, March 1st.
At the base of the Sla
What do we know today about the causes of diseases such as ALS? “It is known that, in order to be functional and stable, proteins must fold up and take on a specific three-dimensional structure, which we can define as biologically active”, Carra explains to Salute. “To do this – he continues – they need the help of other specialized proteins, called molecular chaperones, which assist them in folding and in assuming their final stable conformation, on which our research focuses”.
We have to imagine the inside of the cell as an extremely crowded environment, in which the various components – not only proteins, but also sugars, nucleic acids, etc. – are present in very high concentrations. How does the cell prevent them from interacting with each other in the “wrong” way and forming protein aggregates? Also thanks to the work of these “proteins accompanying other proteins” – the molecular chaperones, in fact.
The matter is not that simple, of course. In fact, this is not the only control mechanism that comes into play, and the high concentration of the components within the cell is not the only reason why protein aggregates can form. “When the cell is subjected to stresses such as changes in pH, salt concentration, oxidative stress, or increased body temperature, proteins can undergo conformational or oxidation state changes, and become more prone to aggregation Added to this are genetic mutations, both inherited and sporadic (those that normally occur during life, ndr.) that can alter the ability of the protein to fold into its correct three-dimensional structure”. An intricate world, says Carra, and still largely to be explored.
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Sometimes “joining” is useful
Complicating matters further is the fact that some proteins are inherently prone to the formation of useful, non-harmful aggregates. In this case we speak of the formation of functional complexes, which must however maintain a certain dynamism in order not to transform into the dysfunctional or even toxic aggregates which are at the basis of the onset of many neurodegenerative diseases.
“The ability to form these condensates – says Carra – and above all to maintain their dynamism, or to be able to dissolve and adapt them, is the basis of the cell’s ability to function and adapt to the environment”. It is therefore a mechanism that the cell must be able to control in a very fine way: our cells have in fact developed many control systems during evolution with the aim of maintaining the so-called homeostasis, or a state of functional equilibrium.
‘If one mechanism is disrupted, the cell will try to compensate by boosting others. However, as sporadic mutations accumulate or as we age, these compensatory mechanisms can become insufficient and fail to prevent disease progression.’ We are talking, recalls Carra, of very complex pathologies, which depend on many different factors.
The importance of mid-career funding
One of the great difficulties for those involved in this type of study is that of obtaining funding. Researchers have to fight with a lack of prizes and funds to support them, especially in the consolidation phase of their laboratories: let’s think of the purchase of specific reagents and instruments, but also of the remuneration of specialized personnel who are able to use them or to ensure its maintenance. This is why grants such as the one from the Armenise Harvard Foundation and Airalzh Onlus are important, which will allow Carra and his collaborators to pursue research to identify specific physiological mechanisms involved above all in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.
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The new prize
The Mid-career Award offers a grant of 100,000 dollars a year for two years (or 200,000 dollars in total) and aims to support the most interesting basic research in the field of neurodegenerative diseases. With a novelty, compared to traditional tenders: it is possible to access the funding only if you are a scientist who has been in charge of an independent laboratory, in Italy, for at least five but no more than 12 years. “I hope that this initiative will inspire national agencies and institutions to pursue a similar path”, concludes the researcher, who also underlines the importance of establishing funding mechanisms that enjoy a certain regularity over time, and which allow one to continue one’s research at long term: “Only in this way is it possible to achieve solid results”. March 1st registrations open for the new Airalzh-Armenise Harvard call for tenders for the two-year period 2023-2024 and the deadline for proposing one’s candidacy will be May 31, 2023.