Myocyte Enhacer Factor 2 Pathway Disruption in Lymphomonocytes of Patients with Sporadic and Familial Form of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neuro-muscular disease characterized by motor neuron loss. Since MEF2D and MEF2C are members of the myocyte enhancer factor 2 (MEF2) family, a group of transcriptional factors playing a crucial role both in muscle and in neural development and maintenance, a possible their involvement in ALS context has been investigated. Based on the knowledge that the transcriptional activity of each tissue specific MEF2 isoform is conserved in different cell types, we choose to assess MEF2D/MEF2C expression in peripheral blood mononuclear cells (PBMC) obtained from 30 sporadic ALS patients (sALS), 9 familial ALS patients with mutations in SOD1 gene (SOD1+ ALS) and 30 healthy controls. Gene expression analysis showed a significant up-regulation for MEF2D and MEF2C mRNA levels in both sALS and SOD1+ subjects and a positive correlation between MEF2D-MEF2C mRNA levels was also observed in patients and controls. Although protein levels were unchanged, a different pattern of distribution for MEF2D and MEF2C proteins in patient PBMC was found, suggesting a possible lack of their function. To evaluate the transcriptional activity of these factors, mRNA levels of their downstream targets BDNF, KLF6, RUFY3 and NPEPPS were assessed. Our results showed a significant down-regulation of BDNF, KLF6 and RUFY3 levels reinforcing the hypothesis that the transcriptional activity of both MEF2D and MEF2C isoforms is altered in sporadic and familial ALS patients. In conclusion, our results evidenced, for the first time, a systemic alteration of MEF2D and MEF2C pathways in both sporadic and familial ALS patients suggesting a possible involvement of these alterations in ALS pathology. Further studies on MEF2 pathway in affected tissues and animal models are needed to clarify the role of this pathway dysregulation in disease onset and progression and to identify new promising therapeutic targets.