PXD031964-1

PXD031964 is an original dataset announced via ProteomeXchange.

Title	UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS
Description	Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disease characterized by motor neuron dysfunction and loss, leading to progressive paralysis and death. A portion of ALS cases is caused by mutation of the proteasome shuttle factor Ubiquilin 2 (UBQLN2), but the molecular pathway leading from UBQLN2 dysfunction to neurodegenerative disease remains unclear. Here, we demonstrate a major function of UBQLN2 in regulating activity of the domesticated gag-pol retrotransposon ‘paternally expressed gene 10’ (PEG10) in human cells and tissues. UBQLN2 exclusively facilitates degradation of the frameshifted gag-pol form of PEG10 through recognition of a unique polyproline repeat. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated ‘nucleocapsid’ fragment, which uniquely localizes to the nucleus. Overexpression of the nucleocapsid fragment upregulates transcription of neuronal genes involved in axon remodeling, which were also affected in sporadic ALS (sALS) patient tissues. Finally, proteomics of spinal cords from ALS patients revealed that PEG10 gag-pol is significantly elevated in disease compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through regulation of neuronal gene expression, and restraint of PEG10 as a primary function of UBQLN2.
HostingRepository	PRIDE
AnnounceDate	2023-03-24
AnnouncementXML	Submission_2023-03-23_20:29:02.668.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	ShannonLeslie
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-01 10:00:24	ID requested
⏵ 1	2023-03-23 20:29:03	announced
2	2023-11-14 08:55:53	announced	2023-11-14: Updated project metadata.

submitter keyword: Q-Exactive HF-X, TMT, ALS,Human spinal cord

AlexandraWhiteley
contact affiliation	Biochemistry, University of Colorado, Boulder
contact email	Alexandra.Whiteley@colorado.edu
lab head
ShannonLeslie
contact affiliation	University of Colorado, Boulder
contact email	shannon.n.leslie@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031964
     1. Label: PRIDE project
     2. Name: UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS