PXD071117

PXD071117 is an original dataset announced via ProteomeXchange.

Title	Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration
Description	Aberrant aggregation of the prion-like RNA-binding protein TDP-43 drives several fatal neurodegenerative proteinopathies, including amyotrophic lateral sclerosis (ALS). Here, we define how short, specific RNAs solubilize TDP-43. These short RNAs engage and stabilize the TDP-43 RNA-recognition motifs, which allosterically destabilizes a conserved helical region in the prion-like domain, thereby promoting aggregation-resistant conformers. Sequence-space mining identified short RNA chaperones with enhanced activity against TDP-43 and disease-linked variants. Enhanced short RNA chaperones mitigate aberrant TDP-43 phenotypes in optogenetic models and in ALS patient–derived and control motor neurons. In mice experiencing cytoplasmic TDP-43 aggregation and motor neuron loss, an enhanced short RNA chaperone reduces pathological aggregation, restores TDP-43 function, and confers neuroprotection. These findings define a mechanistic and therapeutic framework for RNA-based strategies to counter TDP-43 proteinopathies.
HostingRepository	PRIDE
AnnounceDate	2026-05-15
AnnouncementXML	Submission_2026-05-15_11:13:59.534.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Katie Copley
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Escherichia coli; NCBI TaxID: NEWT:562;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2025-11-24 00:28:25	ID requested
⏵ 1	2026-05-15 11:14:00	announced

10.1126/science.adv3301;

Copley KE, Mauna JC, Danielson HL, Chen Q, Ozguney B, Ngo M, Xie L, Smirnov A, Davis M, Mayne L, Linsenmeier M, Rubien JD, Bergmann CA, Portz B, Lee BL, Odeh HM, Lai L, Chang YW, Hallegger M, Ule J, Pasinelli P, Poon Y, Mittal J, Fawzi NL, Black BE, Donnelly CJ, Jensen BK, Shorter J, Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration. Science, 392(6798):eadv3301(2026) [pubmed]

submitter keyword: TDP-43, hydrogen/deuterium-exchange mass spectrometry, RNA

James Shorter
contact affiliation	Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
contact email	jshorter@pennmedicine.upenn.edu
lab head
Katie Copley
contact affiliation	Yale University
contact email	katie.copley@yale.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/2026/05/PXD071117

PRIDE project URI

• PRIDE
  1. PXD071117
     1. Label: PRIDE project
     2. Name: Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration