Searching across hundreds of databases

Our searching services are busy right now. Your search will reload in five seconds.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains.

Cell | Apr 19, 2018

RNA-binding proteins (RBPs) with prion-like domains (PrLDs) phase transition to functional liquids, which can mature into aberrant hydrogels composed of pathological fibrils that underpin fatal neurodegenerative disorders. Several nuclear RBPs with PrLDs, including TDP-43, FUS, hnRNPA1, and hnRNPA2, mislocalize to cytoplasmic inclusions in neurodegenerative disorders, and mutations in their PrLDs can accelerate fibrillization and cause disease. Here, we establish that nuclear-import receptors (NIRs) specifically chaperone and potently disaggregate wild-type and disease-linked RBPs bearing a NLS. Karyopherin-β2 (also called Transportin-1) engages PY-NLSs to inhibit and reverse FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2 fibrillization, whereas Importin-α plus Karyopherin-β1 prevent and reverse TDP-43 fibrillization. Remarkably, Karyopherin-β2 dissolves phase-separated liquids and aberrant fibrillar hydrogels formed by FUS and hnRNPA1. In vivo, Karyopherin-β2 prevents RBPs with PY-NLSs accumulating in stress granules, restores nuclear RBP localization and function, and rescues degeneration caused by disease-linked FUS and hnRNPA2. Thus, NIRs therapeutically restore RBP homeostasis and mitigate neurodegeneration.

Pubmed ID: 29677512 RIS Download

Research tools detected in this publication

Data used in this publication

None found

Associated grants

  • Agency: NINDS NIH HHS, Id: R21 NS090205
  • Agency: NINDS NIH HHS, Id: R21 NS094921
  • Agency: NINDS NIH HHS, Id: R01 NS081303
  • Agency: NINDS NIH HHS, Id: F31 NS079009
  • Agency: NINDS NIH HHS, Id: R21 NS100055
  • Agency: NINDS NIH HHS, Id: R01 NS087227
  • Agency: NINDS NIH HHS, Id: R35 NS097974
  • Agency: NIGMS NIH HHS, Id: R01 GM099836
  • Agency: NINDS NIH HHS, Id: R35 NS097263
  • Agency: NIGMS NIH HHS, Id: T32 GM008275
  • Agency: NIGMS NIH HHS, Id: T32 GM071339
  • Agency: NIGMS NIH HHS, Id: R01 GM069909

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

This is a list of tools and resources that we have found mentioned in this publication.


NIH Image

Public image processing and analysis program for Macintosh.

tool

View all literature mentions

Image Studio Lite

A software application which can analyze basic Western blot data and export them for use in spreadsheet programs. Users can create standardized or custom lab reports and can share them with colleagues. Various versions are available and are more compatible with Odyssey and Pearl families of imaging systems, Aerius, and the C‑DiGit Blot Scanner. Optional software keys are also available. Tutorials and support are available on the website.

tool

View all literature mentions

GraphPad Prism

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

tool

View all literature mentions

Microsoft Excel

Software application with data analysis tools and spreadsheet templates to track and visualize data. It is used to manage and process data.

tool

View all literature mentions