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

journal.pgen.1006805.g001

by Sei-Kyoung Park, Joo Y. Hong, Fatih Arslan, Vydehi Kanneganti, Basant Patel, Alex Tietsort, Elizabeth M. H. Tank, Xingli Li, Sami J. Barmada, Susan W. Liebman

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.2rLDZau

from #Medicine-SfakianakisAlexandros via o.lakala70 on Inoreader http://ift.tt/2rLy6Kl
via IFTTT Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174

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