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


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.

SUBMITTER: Park SK 

PROVIDER: S-EPMC5460882 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Park Sei-Kyoung SK   Hong Joo Y JY   Arslan Fatih F   Kanneganti Vydehi V   Patel Basant B   Tietsort Alex A   Tank Elizabeth M H EMH   Li Xingli X   Barmada Sami J SJ   Liebman Susan W SW  

PLoS genetics 20170522 5


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 t  ...[more]

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