PXD051922

PXD051922 is an original dataset announced via ProteomeXchange.

Title	Comparative interactome analyses of ALS proteins help define the pathogenic effects of mutant C21ORF2 in motor neurons.
Description	Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease leading to motor neuron loss. It has a strong genetic contribution, but most ALS-associated gene mutations remain poorly characterized. Therefore, we performed comparative interactome analyses of recently discovered ALS-associated proteins which highlighted many novel binding partners, and both unique and shared interactors. This suggests that different ALS-associated proteins can act through distinct and/or similar cellular pathways. The analysis identified C21ORF2 as a strongly connected protein. The role of C21ORF2 mutations in ALS is largely unknown. Our data show C21ORF2 expression in affected neurons and that the prominent C21ORF2-V58L variant induces apoptosis in mouse neurons and movement defects in zebrafish embryos. iPSC-derived motor neurons from C21ORF2-V58L-ALS patients, but not isogenic controls, show increased apoptosis, and changes in DNA damage response (DDR), mitochondria and electrophysiological properties. In addition, C21ORF2-V58L induced post-transcriptional downregulation of NEK1, an ALS-associated protein implicated in apoptosis and DDR. In all, our data define the pathogenic effects of C21ORF2-V58L and implicate reduced NEK1 levels, due to impaired proteosomal degradation, downstream of this ALS mutation.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:57:42.824.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Harmjan Vos
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-05-01 06:49:51	ID requested
1	2024-09-05 05:31:01	announced
⏵ 2	2024-10-22 06:57:43	announced	2024-10-22: Updated project metadata.

10.1186/S40478-024-01852-6;

submitter keyword: Amyotrophic lateral sclerosis/ Genetic mutation/ Interactor/ IPSC/ Motor neuron

Jeroen Pasterkamp
contact affiliation	Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands
contact email	r.j.pasterkamp@umcutrecht.nl
lab head
Harmjan Vos
contact affiliation	University Medical Center Utrecht Dept. Molecular Cancer Research
contact email	h.r.vos-3@umcutrecht.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD051922
     1. Label: PRIDE project
     2. Name: Comparative interactome analyses of ALS proteins help define the pathogenic effects of mutant C21ORF2 in motor neurons.