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

Serio, T R and Park, S-K and Hong, J Y and Arslan, F and Kanneganti, V and Patel, Basant Kumar and Tietsort, A and Tank, E M H and Li, X and Barmada, S J and Liebman, S W (2017) Overexpression of the essential Sis1 chaperone reduces TDP-43 effects on toxicity and proteolysis. PLOS Genetics, 13 (5). e1006805. ISSN 1553-7404

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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.

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IITH Creators:

IITH Creators	ORCiD
Patel, Basant Kumar	http://orcid.org/0000-0001-9465-4803

Item Type:

Article

Additional Information:

We thank R.B. Wickner, M. Tanaka, S. Lindquist, A. Gitler, E.A. Craig, S.H. Park D. C. Masison, Shulin Ju and L. Li for strains, plasmids and antibodies.

Uncontrolled Keywords:

AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; PROTEIN MISFOLDING DISEASES; SACCHAROMYCES-CEREVISIAE; PRION PROPAGATION; STRESS GRANULES; YEAST MODEL; NEURODEGENERATIVE-DISEASES; POLYGLUTAMINE AGGREGATION; CELLULAR TOXICITY

Subjects:

Others > Biotechnology

Divisions:

Department of Biotechnology

Depositing User:

Team Library

Date Deposited:

30 Jun 2017 07:10

Last Modified:

10 Nov 2017 06:34

URI:

http://raiithold.iith.ac.in/id/eprint/3316