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PLoS Genet. 2017 May 22;13(5):e1006805. doi: 10.1371/journal.pgen.1006805. eCollection 2017 May.

Overexpression of the essential Sis1 chaperone reduces TDP-43 effects on toxicity and proteolysis.

Author information

1
Department of Pharmacology, University of Nevada, Reno, Nevada, United States of America.
2
Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, United States of America.
3
Department of Biochemistry and Molecular Biology, University of Nevada, Reno, Nevada, United States of America.
4
Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America.

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.

PMID:
28531192
PMCID:
PMC5460882
DOI:
10.1371/journal.pgen.1006805
[Indexed for MEDLINE]
Free PMC Article

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