Studies of the effects of mutant p97/VCP on human motor neurons.

To uncover the molecular mechanisms that underlie the effects of mutant p97 on human MNs and search for potential treatments, we differentiated iPSCs derived from IBMPFD patients. These cells, which carry the p97R155H/+ mutation, were compared to isogenic wild type (isoWT) control MNs. We evaluated MN survival and relevant p97 cellular functions. Proteomic and transcriptomic analyses were also performed to explore the broader effects of this disease-linked p97 mutation in human MNs. Lastly, we tested the protective effects of p97 inhibitors on p97R155H/+ MNs and found that p97 inhibitors rescue the neuron loss and restore dysregulated protein levels in p97R155H/+ MNs. Our results provide insight into the effects of p97 mutants in MNs, and suggest a possible new therapeutic avenue for treating IBMPFD.