Advances in the understanding of spinal muscular atrophy by Denis Mottet's team in collaboration with French and Canadian researchers

Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disorder affecting nerves and muscles. It is characterized by the degeneration of motor neurons in the spinal cord. This loss of motor neurons prevents muscles from receiving signals, leading to progressive, debilitating muscle atrophy. This disabling neuromuscular disease affects several thousand patients in Europe. It is the most common cause of fatal hereditary disease in children, usually resulting in death within the first year of life.

SMA is caused by mutations in the SMN1 gene, which codes for the Survival of Motor Neuron (SMN) protein. In the nucleus of cells, the SMN protein is located in a small organelle called Cajal bodies, which can itself associate with the nucleolus. It performs several essential functions in the cell, such as the assembly of numerous ribonucleoprotein complexes associated with RNA transport, messenger RNA splicing and ribosomal RNA biogenesis. It is therefore fundamental to cellular homeostasis. 

The nucleolus is a nuclear sub-compartment essential for the transcription of ribosomal DNA (rDNA) and the early maturation of ribosomal RNA (rRNA). These two processes are critical steps in the production of ribosomes, which are the sites of protein synthesis in the cell. The nucleolus is a highly organized, dynamic structure that can be altered by a variety of environmental stresses. DNA-damaging agents such as ultraviolet rays, cigarette smoke or various pollutants cause rDNA to be exported to the periphery of the nucleolus for repair. Once this repair is complete, the rDNA resumes its place in the nucleolus, and the nucleolar structure is correctly restored.

Following a fruitful international collaboration, French (Dr. Giuseppina Giglia-Mari, Université Claude Bernard Lyon 1, Lyon) and Canadian (Dr. Jocelyn Coté, University of Ottawa) research groups, in collaboration with Dr. Denis Mottet's group (Gene Expression and Cancer Laboratory, GIGA-MBD), have recently published in Nature Communications a study demonstrating that a functional SMN protein in healthy motor neurons is essential for adequate restoration of nucleolus structure after cellular stress. On the other hand, in cells from SMA patients carrying SMN mutations, rDNA dislocated at the edge of the nucleolus during UV stress can no longer return to its initial position, and nucleolus structure is not restored.

Given that the structure of the nucleolus is very important for ribosome formation and optimal protein production, it is important to determine at the molecular level the impact of mutations in the SMN protein on all the mechanisms leading to protein synthesis (transcription - splicing - translation) during cellular stress in SMA patients.  To answer this question, the 3 laboratories have just been jointly awarded transnational PINT/multi - JPND Research 2023 funding (EU Joint Program Neurodegenerative Research - European Union's Horizon 2020 research). They hope to gain a better understanding of the functional link(s) between RNA metabolism and the processes responsible for motor neuron degeneration in spinal muscular atrophy.

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