venerdì, Settembre 29, 2023

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Wanna fight neurodegeneration? SUMO is not the right style

Studying the fundamental aspects of biology can sometimes lead to unexpected findings that directly relate to human disease. In one of the latest examples of scientific serendipity, researchers from the Salk Institute found that an important quality control mechanism in baker’s yeast is closely connected to hypomyelinating leukodystrophy, a debilitating disease found in children. The findings, reported September 7, 2018, in the journal eLife, could indicate a therapeutic approach for this rare disease, as well as for multiple sclerosis and other neurodegenerative diseases. Research weas led by the senior author professor Tony Hunter, Salk American Cancer Society. In the face of genetic damage, from to neurodegeneration, cells mobilize molecular processes that act as repair crews. For the past decade or so, one focus of Hunter’s lab has been the study of certain proteins that regulate these repair procedures through a process called sumoylation. SUMO addition to proteins (a molecular “tagging”), acts as a quality-control mechanism to signal to a cell that the protein should be cleared out.

In the current study, Dr Hunter and his team set up a genetic screening test in yeast to determine which proteins relied on sumoylation to function properly. He identified several subunits of a protein complex called RNA polymerase III–which plays an important role in copying DNA into RNA–among those that were affected. The team found that when Pol III was mutated the cells stop growing, because the mutant Pol III cannot make enough transfer RNAs (small RNAs that are needed for cells to synthesize proteins). However, that defect could be rescued by reducing sumoylation in the yeast cells. At the same time the research with Pol III was going on Hunter’s lab, other groups studying hypomyelinating leukodystrophy–a neurodegenerative disease characterized by the loss of the protective insulation around nerve cells (myelin)–discovered that the condition was caused by mutations in Pol III. Although Pol III was known to be important for the regulation of cell growth, this was the first time a specific disease had been connected with defects in Pol III.

Due to the loss of myelin insulation around nerves, people with hypomyelinating leukodystrophy have delayed development, intellectual disabilities and impaired movement. There is currently no therapy available; however, these new findings suggest that one way to limit the effects of these mutations may be to partially inhibit sumoylation, which would in turn block the effects of the mutated Pol III. The research still has a long way to go: sumoylation is important for many other functions as well, so inhibiting it in all cells would not be a useful approach. Furthermore, although the new findings partially explain the loss of myelin due to genetic mutation, the investigators still don’t know why these Pol III mutations affect oligodendrocytes, the cells that coat the nerve axons with myelin in particular. Hunter’s lab is now working with induced pluripotent stem cells (iPSCs) as well as in other types of cells, including cancer cells, to try to gain further insight into the mechanisms that underlie Pol III defects.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Wang Z, Wu C et al. Hunter T. Elife. 2018 Sep 7;7. 

Neyret-Kahn H et al. Genome Res. 2013; 23(10):1563.

Rohira AD et al. J Biol Chem. 2013; 288(26):19288-95.

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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