Spinal Muscular Atrophy Patient iPSC-Derived Motor Neurons Display Altered Proteomes at Early Stages of Differentiation

Spinal muscular atrophy
(SMA) is an autosomal recessive neurodegenerative
disorder characterized by loss of motor neurons (MN) in the spinal
cord leading to progressive muscle atrophy and weakness. SMA is caused
by mutations in the survival motor neuron 1 (SMN1) gene, resulting in reduced levels of survival motor neuron (SMN)
protein. The mechanisms that link SMN deficiency to selective motor
neuron dysfunction in SMA remain largely unknown. We present here,
for the first time, a comprehensive quantitative TMT-10plex proteomics
analysis that covers the development of induced pluripotent stem cell-derived
MNs from both healthy individuals and SMA patients. We show that the
proteomes of SMA samples segregate from controls already at early
stages of neuronal differentiation. The altered proteomic signature
in SMA MNs is associated with mRNA splicing, ribonucleoprotein biogenesis,
organelle organization, cellular biogenesis, and metabolic processes.
We highlight several known SMN-binding partners and evaluate their
expression changes during MN differentiation. In addition, we compared
our study to human and mouse in vivo proteomic studies revealing distinct
and similar signatures. Altogether, our work provides a comprehensive
resource of molecular events during early stages of MN differentiation,
containing potentially therapeutically interesting protein expression
profiles for SMA.