Overexpression of the essential Sis1 chaperone reduces TDP-43 effects on toxicity and proteolysis
Loading...
Authors
Park, Sei-Kyoung
Hong, Joo Y.
Arslan, Fatih
Kanneganti, Vydehi
Patel, Basant
Tietsort, Alex
Tank, Elizabeth M. H.
Li, Xingli
Barmada, Sami J.
Liebman, Susan W.
Issue Date
2017
Type
Article
Language
Keywords
Alternative Title
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by selective loss of motor neurons with inclusions frequently containing the RNA/DNA binding protein TDP-43. Using a yeast model of ALS exhibiting TDP-43 dependent toxicity, we now show that TDP-43 overexpression dramatically alters cell shape and reduces ubiquitin dependent proteolysis of a reporter construct. Furthermore, we show that an excess of the Hsp40 chaperone, Sis1, reduced TDP-43's effect on toxicity, cell shape and proteolysis. The strength of these effects was influenced by the presence of the endogenous yeast prion, [PIN+]. Although overexpression of Sis1 altered the TDP-43 aggregation pattern, we did not detect physical association of Sis1 with TDP-43, suggesting the possibility of indirect effects on TDP-43 aggregation. Furthermore, overexpression of the mammalian Sis1 homologue, DNAJB1, relieves TDP-43 mediated toxicity in primary rodent cortical neurons, suggesting that Sis1 and its homologues may have neuroprotective effects in ALS.
Description
Citation
Park, S.-K., Hong, J. Y., Arslan, F., Kanneganti, V., Patel, B., Tietsort, A., … Liebman, S. W. (2017). Overexpression of the essential Sis1 chaperone reduces TDP-43 effects on toxicity and proteolysis. PLOS Genetics, 13(5), e1006805. doi:10.1371/journal.pgen.1006805
Publisher
License
Creative Commons Attribution 4.0 International
Journal
Volume
Issue
PubMed ID
ISSN
1553-7404