Heat Shock Protein Grp78/BiP/HspA5 Binds Directly to TDP-43 and Mitigates Toxicity Associated with Neurodegenerative Disease Pathology

Liberty François-Moutal, David Scott, Andrew Ambrose, Christopher Zerio, Kumara Dissanayake, Danielle May, Jacob Carlson, Edward Barbieri, Aubin Moutal, Kyle Roux, James Shorter, Rajesh Khanna, Sami Barmada, Leeanne McGurk (Lead / Corresponding author), May Khanna (Lead / Corresponding author)

Research output: Working paper/PreprintPreprint

38 Downloads (Pure)

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure or effective treatment in which TAR DNA Binding Protein of 43 kDa (TDP-43) abnormally accumulates into misfolded protein aggregates in affected neurons. It is widely accepted that protein misfolding and aggregation promote proteotoxic stress. The molecular chaperones are the body’s primary line of defense against proteotoxic stress and there has been long-standing interest in understanding the relationship between chaperones and aggregated protein in ALS. Of particular interest are the heat shock protein of 70 kDa (Hsp70) family of chaperones; however, defining which of the 13 human Hsp70 isoforms is critical for ALS, has presented many challenges. To gain insight into the specific Hsp70 that modulates TDP-43, we investigated the relationship between TDP-43 and the Hsp70s using proximity-dependent biotin identification (BioID) and discovered several Hsp70 isoforms associated with TDP-43 in the nucleus, raising the possibility of an interaction with native TDP-43. We further found that HspA5 bound specifically to the RNA-binding domain of TDP-43 using recombinantly expressed proteins. HspA5 is increased in prefrontal cortex neurons of ALS patients. Finally, overexpression of HspA5 in Drosophila rescued TDP-43-induced toxicity, suggesting that upregulation of HspA5 may have a compensatory role in ALS pathobiology.

Original languageEnglish
PublisherResearch Square
Number of pages38
DOIs
Publication statusPublished - 8 Dec 2021

Keywords

  • TDP43
  • Hsp70
  • HspA5
  • BiP
  • GRP78
  • binding interface
  • ALS
  • chaperone

Fingerprint

Dive into the research topics of 'Heat Shock Protein Grp78/BiP/HspA5 Binds Directly to TDP-43 and Mitigates Toxicity Associated with Neurodegenerative Disease Pathology'. Together they form a unique fingerprint.

Cite this