Result

The project, based on a multi-omics approach, explored the molecular pathology of MSS, identifying biomarkers and therapeutic targets. Proteomic, metabolomic and transcriptomic analysis of blood and fibroblasts detected metabolites, genes and proteins with differential expression between patients and controls: biomarkers and potential therapeutic targets. Bioinformatic analyses showed alterations in key pathways, including serine synthesis, autophagy, antioxidant response, extracellular matrix (ECM) and cytoskeleton remodeling (see data).

ECM and cytoskeleton involvement in MSS was confirmed in patient fibroblasts, showing reduced motility and matrix remodeling capacity. TEM analysis revealed structural alterations of the ECM, while study of the myotendinous junction in the MSS mouse model (woozy) showed disorganization of collagen fibers. The abnormality of the ECM represents a key pathological aspect of MSS, as it could impair central nervous system and skeletal muscle function (see publication (Amodei et al. 2024)).

Study of the activities of enzymes involved in ROS scavenging confirmed the increase in CAT and SOD and found a reduction in GPx and GR. The new antioxidant set-up, in patient fibroblasts, was associated with reduced levels of ROS and oxidative damage to lipids, proteins, and DNA comparable to controls. In the muscle of the 'woozy' mouse, changes similar to those detected in the patient's fibroblasts were observed, helping to define the pathological mechanisms of this syndrome.

In addition, by omics analysis and functional experiments, a novel variant of SIL1 with unknown significance (p.E342K) was classified as pathological. 

Finally, the Woozy mouse was given a serine supplement to compensate for the metabolic deficiency revealed by omics studies, without observing motor or behavioral improvements.

Amodei L, Ruggieri AG, Potenza F, Viele M, Dufrusine B, Franciotti R, Pietrangelo L, Ardini M, Stuppia L, Federici L, De Laurenzi V, Sallese M (2024) Sil1-deficient fibroblasts generate an aberrant extracellular matrix leading to tendon disorganisation in Marinesco-Sjogren syndrome. J Transl Med 22: 787. doi: 10.1186/s12967-024-05582-0