Spinal Muscular Atrophy Patient iPSC-derived Motor Neurons Display Altered Proteins at Early Stages of Differentiation

ABSTRACT: Spinal muscular atrophy (SMA) is characterized by low levels of survival motor neuron (SMN) protein and loss of motor neurons (MN); however, the underlying mechanism that links SMN deficiency to selective motor neuronal dysfunction is still largely unknown. We present here, for the first time, a comprehensive quantitative mass spectrometry study that covers the development of iPSC-derived MNs from both healthy individuals and SMA patients. We show an altered proteomic signature in SMA already at early stages during MN differentiation, associated with ER to Golgi transport, mRNA splicing and protein ubiquitination, in line with known SMA phenotypes. These alterations in the SMA proteome increase further towards later stages of MN differentiation. In addition, we find differences in altered protein expression between SMA patients, which however, have similar biological functions. Finally, we highlight several known SMN-binding partners as well as proteins associated with ubiquitin-mediated proteolysis and evaluate their expression changes during MN differentiation. Altogether, our work provides a rich resource of molecular events during early stages of MN differentiation, containing potentially therapeutically interesting protein expression profiles for SMA.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Stem Cell

DISEASE(S): Spinal Muscular Atrophy

SUBMITTER: Suzy Varderidou  

LAB HEAD: Maarten Altelaar

PROVIDER: PXD015115 | Pride | 2022-02-15

REPOSITORIES: Pride