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 promotes proteotoxic stress. The molecular chaperones are a 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. Moreover, in a Drosophila strain that mimics ALS upon TDP-43 expression, the mRNA levels of the HspA5 homologue (Hsc70.3) were significantly increased. Similarly we observed upregulation of HspA5 in prefrontal cortex neurons from human 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.

Details

Title
Heat shock protein Grp78/BiP/HspA5 binds directly to TDP-43 and mitigates toxicity associated with disease pathology
Author
François-Moutal Liberty 1 ; Scott, David Donald 1 ; Ambrose, Andrew J 2 ; Zerio, Christopher J 2 ; Rodriguez-Sanchez, Marina 3 ; Dissanayake Kumara 4 ; May, Danielle G 5 ; Carlson, Jacob M 1 ; Barbieri, Edward 6 ; Aubin, Moutal 1 ; Roux, Kyle J 7 ; Shorter, James 8 ; Khanna Rajesh 1 ; Barmada, Sami J 9 ; McGurk Leeanne 4 ; Khanna, May 10 

 University of Arizona, Department of Pharmacology, College of Medicine, Tucson, USA (GRID:grid.134563.6) (ISNI:0000 0001 2168 186X); Center for Innovation in Brain Science, Tucson, USA (GRID:grid.134563.6) 
 University of Arizona, Pharmacology and Toxicology, School of Pharmacy, Tucson, USA (GRID:grid.134563.6) (ISNI:0000 0001 2168 186X) 
 NYU, Department of Molecular Pathobiology, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753) 
 University of Dundee, Cell and Developmental Biology, School of Life Sciences, Dundee, UK (GRID:grid.8241.f) (ISNI:0000 0004 0397 2876) 
 Sanford Research, Enabling Technologies Group, Sioux Falls, USA (GRID:grid.430154.7) (ISNI:0000 0004 5914 2142) 
 University of Pennsylvania, Department of Biochemistry and Biophysics, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
 Sanford Research, Enabling Technologies Group, Sioux Falls, USA (GRID:grid.430154.7) (ISNI:0000 0004 5914 2142); University of South Dakota, Department of Pediatrics, Sanford School of Medicine, Sioux Falls, USA (GRID:grid.267169.d) (ISNI:0000 0001 2293 1795) 
 University of South Dakota, Department of Pediatrics, Sanford School of Medicine, Sioux Falls, USA (GRID:grid.267169.d) (ISNI:0000 0001 2293 1795) 
 University of Michigan, Department of Neurology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
10  University of Arizona, Department of Pharmacology, College of Medicine, Tucson, USA (GRID:grid.134563.6) (ISNI:0000 0001 2168 186X); Center for Innovation in Brain Science, Tucson, USA (GRID:grid.134563.6); NYU, Department of Molecular Pathobiology, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753); NYU, Department of Molecular Pathobiology, College of Dentistry, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2665419711
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.