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

PLoS Genetics
Sei-Kyoung ParkSusan W Liebman

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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Citations

Oct 14, 2017·Current Genetics·Tatyana A RyzhovaAlexey P Galkin
Apr 3, 2019·Brain : a Journal of Neurology·Rudolf C HergesheimerHélène Blasco
Jan 9, 2019·Frontiers in Molecular Neuroscience·Zachary T MonahanFrank P Shewmaker
Mar 7, 2019·Frontiers in Molecular Neuroscience·Archana PrasadBasant K Patel
Oct 1, 2020·Neuroscience Insights·Mara-Luciana Floare, Scott P Allen
Jun 21, 2020·Nature Communications·Yeonkyoung ParkYoon Ki Kim
Sep 24, 2020·Molecular Biology of the Cell·Amanjot SinghRandolph Y Hampton
Nov 25, 2020·Proceedings of the National Academy of Sciences of the United States of America·Jinge GuDan Li
Nov 17, 2020·IScience·Natalie E FarrawellJustin J Yerbury
Mar 25, 2019·Journal of Molecular Biology·Sei-Kyoung ParkSusan W Liebman
Mar 2, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Vidhya BharathiBasant K Patel
Apr 29, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Lilian Tsai-Wei LinMartin L Duennwald
Apr 30, 2021·Frontiers in Cellular Neuroscience·Caterina PeggionRaffaele Lopreiato

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Methods Mentioned

BETA
electrophoresis
fluorescence microscopy
genetic modifications
PCR
Transfection

Software Mentioned

ImageJ
μManager
R
Fiji

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