Overexpression of a conserved HSP40 chaperone reduces toxicity of several neurodegenerative disease proteins

TDP-43 and FUS are DNA/RNA binding proteins associated with neuronal inclusions in amyotrophic lateral sclerosis (ALS) patients. Other neurodegenerative diseases are also characterized by neuronal protein aggregates, e.g. Huntington's disease, associated with polyglutamine (polyQ) expansions in...

Full description

Saved in:
Bibliographic Details
Published in:Prion 2018-01, Vol.12 (1), p.16-22
Main Authors: Park, Sei-Kyoung, Arslan, Fatih, Kanneganti, Vydehi, Barmada, Sami J., Purushothaman, Pravinkumar, Verma, Subhash Chandra, Liebman, Susan W.
Format: Article
Language:English
Subjects:
amyotrophic lateral sclerosis
Animals
Asparagine - metabolism
chaperone
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
DNAJB1
Extra View
FUS
Glutamine - metabolism
HEK293 Cells
HSP40 Heat-Shock Proteins - genetics
HSP40 Heat-Shock Proteins - metabolism
Humans
Neurodegenerative Diseases - metabolism
Neurons - metabolism
Peptides - metabolism
PIN
Prions - metabolism
Protein Aggregates
RNA-Binding Protein FUS - genetics
RNA-Binding Protein FUS - metabolism
Sis1
TDP-43
Ubiquitin - metabolism
Ubiquitin Proteasome System (UPS)
yeast
Yeasts
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:TDP-43 and FUS are DNA/RNA binding proteins associated with neuronal inclusions in amyotrophic lateral sclerosis (ALS) patients. Other neurodegenerative diseases are also characterized by neuronal protein aggregates, e.g. Huntington's disease, associated with polyglutamine (polyQ) expansions in the protein huntingtin. Here we discuss our recent paper establishing similarities between aggregates of TDP-43 that have short glutamine and asparagine (Q/N)-rich modules and are soluble in detergents, with those of polyQ and PIN4C that have large Q/N-rich domains and are detergent-insoluble. We also present new, similar data for FUS. Together, we show that like overexpression of polyQ or PIN4C, overexpression of FUS or TDP-43 causes inhibition of the ubiquitin proteasome system (UPS) and toxicity, both of which are mitigated by overexpression of the Hsp40 chaperone Sis1. Also, in all cases toxicity is enhanced by the [PIN + ] prion. In addition, we show that the Sis1 mammalian homolog DNAJBI reduces toxicity arising from overexpressed FUS and TDP-43 respectively in human embryonic kidney cells and primary rodent neurons. The common properties of these proteins suggest that heterologous aggregates may enhance the toxicity of a variety of disease-related aggregating proteins, and further that chaperones and the UPS may be key therapeutic targets for diseases characterized by protein inclusions.
ISSN:1933-6896
1933-690X
DOI:10.1080/19336896.2017.1423185