Amyotrophic lateral sclerosis, known as ALS, is a neurodegenerative disorder that affects motor neurons. These are the neuronal cells responsible for muscle innervation, whose degenerations leads to progressive paralysis culminating with motor and respiratory failure.

Two forms of ALS can be identified: the familial form, which is due to specific genetic mutations, and the sporadic form, whose pathogenesis is not related to clear genetic family history and whose causes are still mostly unknown. Although numerous studies have allowed the characterisation of various proteins involved in ALS, there is still much to discover regarding the complexity of the onset and progression of the disease, and above all, on its possible treatment.

The research team belonging to the Charles Darwin Department of Biology and Biotechnology of Sapienza University of Rome and the Centre for Life Nano- & Neuro-Science of the Italian Institute of Technology (IIT) of Rome coordinated by Irene Bozzoni, in collaboration with Mariangela Morlando of the University of Perugia, has added a new piece in the understanding of this pathology, identifying the circular RNA circ-Hdgfrp3 as a new molecular component of the pathological aggregates that are characteristic of ALS.

This type of RNA has been named "circular" due to its peculiar shape, which endows it with particular resistance to degradation. They represent a new class of molecules expressed in all cells, particularly in the nervous system, where their malfunctioning has been associated with different pathological states.

The study published in the journal iScience analyses the presence of this specific circular RNA in association with ALS: more precisely, it was identified within the pathological aggregates produced by mutations of the FUS protein that are associated with a severe form of the disease. Indeed, the FUS protein, which generally localises in the nucleus, is found in the cytoplasm due to specific mutations. Here, it can aggregate, forming large inclusions typical of ALS, which sequester many cellular components, preventing their correct localisation and function.

The research group studied the effects of mutations in the FUS protein on the localisation of this circular RNA using advanced imaging techniques and studying motor neurons of animal models reproduced in vitro. While in healthy motor neurons, the circular RNA moves along the extensions of neurons, thus suggesting an important shuttle function to and from the cell's periphery; in pathological conditions, it remains trapped in FUS aggregates. This indicates that the formation of such pathological aggregates can have a deleterious effect on the normal shuttling functions of this circular RNA and thus contribute to the malfunctioning of motor neurons.

"In this study, we have defined the features of this circular RNA – says Irene Bozzoni, head of the Sapienza group – and described the alterations of its intracellular localisation that occur in motor neurons bearing mutations for the FUS protein that are associated to ALS."

This research, financed by the European Research Council (ERC) and the AriSLA Foundation, opens up new interesting frontiers for understanding neurodegenerative disorders concerning the role of pathological aggregates and the RNAs contained within them.

References: 

Circ-Hdgfrp3 shuttles along neurites and is trapped in aggregates formed by ALS-associated mutant FUS - Eleonora D’Ambra, Tiziana Santini, Erika Vitiello, Sara D’Uva, Valentina Silenzi, Mariangela Morlando e Irene Bozzoni - iScience 2021 https://doi.org/10.1016/j.isci.2021.103504

Further Information

Irene Bozzoni 
Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome
irene.bozzoni@uniroma1.it