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

• Published in: PLoS genetics 2017-05, Vol.13 (5), p.e1006805
• Main 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
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Analysis; Animals; Biology and Life Sciences; Cell size; Cells, Cultured; Cortex; Deoxyribonucleic acid; Disease; DNA; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene expression; Genetic aspects; Health aspects; Homology; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; Hsp40 protein; Mammals; Medicine and Health Sciences; Molecular chaperones; Motor neurons; Motor task performance; Mutation; Nervous system diseases; Neurology; Neurons; Neurons - metabolism; Neuroprotection; Pharmacology; Physical Sciences; Protein Binding; Proteins; Proteolysis; Rats; Rats, Long-Evans; Research and Analysis Methods; Ribonucleic acid; Risk factors; RNA; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Sclerosis; Toxicity; Ubiquitin; Ubiquitin - metabolism; Yeast
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006805

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.