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

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. © 2017 park et al.