Pathologic alterations in the proteome of synaptosomes from a mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a human genetic disorder characterized by muscle weakness, muscle atrophy, and death of motor neurons. SMA is caused by mutations or deletions in a gene called survival motor neuron 1 (SMN1). SMN1 is a housekeeping gene, but the most prominent pathologies in SMA are atrophy of myofibers and death of motor neurons. Further, degeneration of neuromuscular junctions, of synapses, and of axonal regions are features of SMA disease. Here, we have investigated the proteome dynamics of central synapses in P14 Smn(2B/- )mice, a model of SMA. Label-free quantitative proteomics on isolated synaptosomes from spinal cords of these animals identified 2030 protein groups. Statistical data analysis revealed 65 specific alterations in the proteome of the central synapses at the early onset stage of disease. Functional analysis of the dysregulated proteins indicated a significant enrichment of proteins associated with mitochondrial dynamics, cholesterol biogenesis, and protein clearance. These pathways represent potential targets for therapy development with the goal of providing stability to the central synapses, thereby preserving neuronal integrity in the context of SMA disease. Data are available via ProteomeXchange with identifier PXD012850.