Studying the role of stress in amyotrophic lateral sclerosis

Óscar Fernández-Capetillo

Centro Nacional de Investigaciones Oncológicas- CNIO, Spain

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to the progressive loss of motorneurons and for which there is no cure at present. It usually affects one person in 50,000 between the ages of 50 and 60. The prognosis after diagnosis is grim and patients die within three to four years. Although some treatments are available, they have little impact on life expectancy.

As ALS is polygenic in nature, in which several genes are mutated, it is difficult to identify a common mechanism that explains the disease. The first gene discovered to be mutated in this pathology is SOD1, which suppresses oxidative stress. Accordingly, antioxidant treatments were first applied to treat the disease and current therapies focus on reducing oxidative stress. Unfortunately, however, these treatments have only marginal effects on patients’ lifespan. However, besides SOD1, the function of many of the other genes found to be mutated in ALS patients points to problems related to RNA metabolism as the origin of the disease. In fact, one of the most universal markers of ALS is the accumulation of aggregates of TDP-43, an RNA-binding protein.

At the cellular level, a common consequence of mutations affecting RNA metabolism is the appearance of nucleolar stress, as the nucleolus is the cell organelle with the highest concentration of RNA. Indeed, alterations of the nucleolus have often been described in patients with neurodegenerative diseases. In this context, recent studies have shown that reducing nucleolar stress limits age-associated pathologies in animal models. However, the potential of this strategy to treat neurodegenerative diseases has not been investigated in depth. Accordingly, in this project, the researchers will explore the potential value of chemical and genetic strategies to modulate nucleolar function as a possible new therapy for the treatment of amyotrophic lateral sclerosis.

Modulating nucleolar activity and stress responses as a therapeutic strategy in ALS

€498,850