PXD048185

PXD048185 is an original dataset announced via ProteomeXchange.

Title	ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-09-08
AnnouncementXML	Submission_2025-09-07_16:31:31.135.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joao Paulo
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-31 08:39:11	ID requested
⏵ 1	2025-09-07 16:31:32	announced

10.1016/j.stemcr.2024.01.002;

Klickstein JA, Johnson MA, Antonoudiou P, Maguire J, Paulo JA, Gygi SP, Weihl C, Raman M, ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons. Stem Cell Reports, 19(3):366-382(2024) [pubmed]

submitter keyword: UBXD1, lysosome,Human motor neurons, CB-5083, p97

Malavika Raman
contact affiliation	Department of Developmental, Molecular and Chemical Biology Tufts University School of Medicine Boston MA 02111
contact email	malavika.raman@tufts.edu
lab head
Joao Paulo
contact affiliation	Harvard Medical School
contact email	joao_paulo@post.harvard.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/09/PXD048185

PRIDE project URI

• PRIDE
  1. PXD048185
     1. Label: PRIDE project
     2. Name: ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons