Il coinvolgimento dei tessuti periferici nella patogenesi dell'Atrofia Muscolare Spinale: analisi del network mitocondriale e del profilo autofagico in fibroblasti umani.

Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by mutation of the survival motor neuron (SMN) 1 gene, leading to degeneration of lower alpha motor neurons (MNs), muscular atrophy and premature death of the patients. Although MNs seem the most affected cells, several peripheral alterations have been described. Among the others, SMA pathogenesis has been associated with mitochondrial and autophagic dysfunctions: interestingly, alterations in the autophagic processes correlate to changes in mitochondrial content and activity. Hence, the aim of this study was to investigate such alterations in SMA fibroblasts by FACS, immunofluorescence (IF) followed by Mitochondrial Network Analysis (MiNA) and by an enzymatic assay for mitochondrial activity. In SMA mouse embryonic fibroblasts (MEFs), MiNA revealed an increase of mitochondrial footprint (+1 fold) and individuals (almost +4 folds) compared to WT, indicating a significant fragmentation of the network. In human fibroblasts, where the mitochondrial content appears equal between patients and controls, MiNA confirmed the tendency to network fragmentation and the enzymatic activity of the mitochondrial enzyme ACO2 has been found altered in SMA. Interestingly, unlikely what previously observed in MNs, IF did not reveal the activation of the autophagic process. This suggests that in peripheral tissues the accumulation of mitochondrial alterations per se does not activate autophagic processes. Overall, these findings could help in the identification of peripheral biomarkers and new targets for combinatorial therapies for SMA.