PXD055826

PXD055826 is an original dataset announced via ProteomeXchange.

Title	Neuronal aging leads to disrupted RNA metabolism
Description	Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged (i.e. >50 year-old) healthy donors directly into neurons, which retained their aging-associated phenotypes including senescence and dysregulation of CpG methylation. Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially 26 spliceosome components. Intriguingly, splicing proteins – like the dementia and ALS-associated protein TDP-43 – mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Although spliceosome components can be sequestered within cytoplasmic stress granules, we find that aged neurons suffer from chronic stress that leads to the segregation of stress granule and spliceosome RNA-binding proteins. We link chronic stress to the accumulation of misfolded proteins and to poor HSP90α chaperone activity. Importantly, we also show that aged neurons respond poorly to acute stress treatments, leading to long-term retention of stress granules and failure to initiate transcription of stress-related heat shock proteins. Together our data demonstrates that dysregulation of RNA metabolism is a key driver of poor resiliency in aged neurons.
HostingRepository	PRIDE
AnnounceDate	2025-02-19
AnnouncementXML	Submission_2025-02-18_17:27:50.772.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xuezhen Ge
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-12 15:25:47	ID requested
⏵ 1	2025-02-18 17:27:51	announced

Dataset with its publication pending

submitter keyword: Human, neuron, transdifferentiation

Eric J. Bennett
contact affiliation	Department of Cell & Developmental Biology, University of California, San Diego, CA 92093, USA.
contact email	e1bennett@ucsd.edu
lab head
Xuezhen Ge
contact affiliation	University of California San Diego
contact email	x1ge@ucsd.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD055826
     1. Label: PRIDE project
     2. Name: Neuronal aging leads to disrupted RNA metabolism