Research reveals possible link between protein and ALS disease

Cells, the building blocks of our body, contain organelles—small structures performing crucial functions. Until recently, it was believed that organelles were always surrounded by a protective membrane. However, recent discoveries show that membrane-less organelles also exist. These structures, also known as "droplets," form when certain molecules in the cell separate from others through phase separation, similar to how oil and water separate. Membrane-less organelles play vital roles in processes like gene regulation and cellular stress responses.

A notable example of these membrane-less organelles are stress granules—temporary structures formed in cells under stress, such as during viral infections. These granules protect essential molecules until the stress subsides. The protein G3BP1 plays a key role in this process. Margot Van Nerom, from the Structural Biology Brussels research group, conducted a study for her doctoral research investigating the link between ALS and G3BP1's function.

“In a specific form of ALS, called C9-ALS, a mutation in the C9orf72 gene leads to the production of toxic dipeptide repeats. These dipeptides strongly bind to G3BP1, disrupting its normal function and stress granule formation. In ALS patients, these liquid stress granules are not properly broken down, leading to harmful aggregates that impair normal cellular functions,” explains Van Nerom.

“Our findings are based on laboratory studies of isolated proteins and still need to be confirmed in animal models and clinical trials. Nonetheless, this is an important step forward in understanding the role of dipeptide repeats in ALS and other neurodegenerative disorders. Discoveries like this pave the way for the development of new therapeutic interventions,” concludes Van Nerom.

Reference:
M. Van Nerom, J. Ahmed, T. Lazar, A. Meszaros, Q. Galand, W. De Malsche, J. Van Lindt, R. Pancsa, D. Maes, P. Tompa, C9orf72-linked arginine-rich dipeptide repeats aggravate pathological phase separation of G3BP1, 2024, Proc. Natl. Acad. Sci. U.S.A. 121 (50) e2402847121, https://doi.org/10.1073/pnas.2402847121.