Animal models and human post-mortem analysis show activation of the unfolded protein response (UPR) in motor neuron disease (MND). The role the UPR plays in MND caused by mutations in C9ORF72 and TARDBP is poorly understood and it may be detrimental to neuronal survival.Aim
Determine whether induced pluripotent stem cell (iPSC)-derived spinal motor neurons from patients with mutations in C9ORF72 and TARDBP show UPR activation by three weeks post platedown.Methods
IPSCs from control and MND patients with mutation-corrected isogenic pairs were converted into spinal motor neurons using the Nedelec protocol. Survival analysis with calcein AM was determined by baseline imaging and at 24 and 48 hour timepoints for C9ORF72 and TARDBP mutants. PERK, IRE1 and ATF6, markers of endoplasmic reticulum stress, were assessed by Western blotting. XBP activation was probed by qPCR and splicing assays.Preliminary and Results
The project is ongoing but at the time of submission survival in response to tunicamycin doses between 1 µg/mL and 50 µg/mL does not vary significantly between C9ORF72 mutants and their isogenic controls. The TARDBP tunicamycin survival assay is ongoing. ATF6 was significantly upregulated in TARDBP mutants at three weeks but normal in C9ORF72 mutant cells.