Dataset Information

ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons

ABSTRACT: Mutations in the AAA+ ATPase p97 cause multisystem proteinopathy 1 which includes amyotrophic-lateral sclerosis; however, the pathogenic mechanisms that contribute to motor neuron loss remain obscure. Here, we use two induced pluripotent stem cell models differentiated into spinal motor neurons to investigate how p97 mutations perturb the motor neuron proteome. Using quantitative proteomics, we find that motor neurons harboring the p97 R155H mutation have deficits in the selective autophagy of lysosomes (lysophagy). p97 R155H motor neurons are unable to clear damaged lysosomes and have reduced viability. Lysosomes in mutant motor neurons have increased pH compared to wildtype cells. The clearance of damaged lysosomes involves UBXD1-p97 interaction which is disrupted in mutant motor neurons. Finally, inhibition of the ATPase activity of p97 using the inhibitor CB-5083 rescues lysophagy defects in mutant motor neurons. These results add to the evidence that endo-lysosomal dysfunction is a key aspect of disease pathogenesis in p97-related disorders.

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ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

SUBMITTER: Joao Paulo

LAB HEAD: Malavika Raman

PROVIDER: PXD048185 | Pride | 2025-09-08

REPOSITORIES: Pride

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ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons.

Klickstein Jacob A JA Johnson Michelle A MA Antonoudiou Pantelis P Maguire Jamie J Paulo Joao A JA Gygi Steve P SP Weihl Chris C Raman Malavika M

Stem cell reports 20240208 3

Mutations in the AAA+ ATPase p97 cause multisystem proteinopathy 1, which includes amyotrophic lateral sclerosis; however, the pathogenic mechanisms that contribute to motor neuron loss remain obscure. Here, we use two induced pluripotent stem cell models differentiated into spinal motor neurons to investigate how p97 mutations perturb the motor neuron proteome. Using quantitative proteomics, we find that motor neurons harboring the p97 R155H mutation have deficits in the selective autophagy of ...[more]

PMID: 38335961

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