Cdc48/VCP and endocytosis regulate TDP-43 and FUS toxicity and turnover

Guangbo Liu, Aaron Byrd, Amanda N. Warner, Fen Pei, Eman Basha, Allison Buchanan, J. Ross Buchan

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. TDP-43 (TAR DNA-binding protein 43) and FUS (fused in sarcoma) are aggregation-prone RNA-binding proteins that in ALS can mislocalize to the cytoplasm of affected motor neuron cells, often forming cytoplasmic aggregates in the process. Such mislocalization and aggregation are implicated in ALS pathology, though the mechanism(s) of TDP-43 and FUS cytoplasmic toxicity remains unclear. Recently, we determined that the endocytic function aids the turnover (i.e., protein degradation) of TDP-43 and reduces TDP-43 toxicity. Here, we identified that Cdc48 and Ubx3, a Cdc48 cofactor implicated in endocytic function, regulates the turnover and toxicity of TDP-43 and FUS expressed in Saccharomyces cerevisiae. Cdc48 physically interacts and colocalizes with TDP-43, as does VCP, in ALS patient tissue. In yeast, FUS toxicity also depends strongly on endocytic function but not on autophagy under normal conditions. FUS expression also impairs endocytic function, as previously observed with TDP-43. Taken together, our data identify a role for Cdc48/ VCP and endocytic function in regulating TDP-43 and FUS toxicity and turnover. Furthermore, endocytic dysfunction may be a common defect affecting the cytoplasmic clearance of ALS aggregation-prone proteins and may represent a novel therapeutic target of promise.

Original languageEnglish (US)
Article numbere00256-19
JournalMolecular and cellular biology
Volume40
Issue number4
DOIs
StatePublished - Feb 1 2020

Keywords

  • ALS
  • Autophagy
  • Cdc48
  • Endocytosis
  • FTLD
  • FUS
  • TDP-43
  • VCP

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Cdc48/VCP and endocytosis regulate TDP-43 and FUS toxicity and turnover'. Together they form a unique fingerprint.

Cite this