Proteomic characterization of spinal cord synaptoneurosomes from Tg-SOD1/G93A mice supports a role for MNK1 and local translation in the early stages of amyotrophic lateral sclerosis

• Published in: Molecular and cellular neuroscience 2022-12, Vol.123, p.103792-103792, Article 103792
• Main Authors: Casañas, Juan José, Montesinos, María Luz
• Format: Article
• Language: English
• Subjects: ALS; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animals; Disease Models, Animal; iTRAQ; Local translation; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; MNK1; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteomics; SOD1; Spinal cord; Spinal Cord - metabolism; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2022.103792

The isolation of synaptoneurosomes (SNs) represents a useful means to study synaptic events. However, the size and density of synapses varies in different regions of the central nervous system (CNS), and this also depends on the experimental species studied, making it difficult to define a generic protocol for SNs preparation. To characterize synaptic failure in the spinal cord (SC) in the Tg-SOD1/G93A mouse model of amyotrophic lateral sclerosis (ALS), we applied a method we originally designed to isolate cortical and hippocampal SNs to SC tissue. Interestingly, we found that the SC SNs were isolated in a different gradient fraction to the cortical/hippocampal SNs. We compared the relative levels of synaptoneurosomal proteins in wild type (WT) animals, with control (Tg-SOD1) or Tg-SOD1/G93A mice at onset and those that were symptomatic using iTRAQ proteomics. The results obtained suggest that an important regulator of local synaptic translation, MNK1 (MAP kinase interacting serine/threonine kinase 1), might well influence the early stages of ALS. •We evaluated an improved protocol to obtain spinal cord synaptoneurosomes from WT, Tg-SOD1, and Tg-SOD1/G93A mice, a model of amyotrophic lateral sclerosis.•By iTRAQ proteomics, we identified the proteins affected in synaptoneurosomes from Tg-SOD1/G93A mice at the onset of their symptoms and in symptomatic mice.•A significant number of the affected proteins in the samples at onset are targets of MNK1, a protein that influences FMRP-regulated mRNA local translation.•We found reduced levels of MNK1 in spinal cord synaptoneurosomes from Tg-SOD1/G93A mice at the onset of their symptoms, as well as decreased rates of local translation.•We propose that deregulated local synaptic translation controlled by MNK1 might play a role in the early stages of amyotrophic lateral sclerosis.