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About the Authors:
Sei-Kyoung Park
Affiliation: Department of Pharmacology, University of Nevada, Reno, Nevada, United States of America
Joo Y. Hong
Affiliation: Department of Pharmacology, University of Nevada, Reno, Nevada, United States of America
Fatih Arslan
Affiliations Department of Pharmacology, University of Nevada, Reno, Nevada, United States of America, Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, United States of America
Vydehi Kanneganti
Affiliation: Department of Pharmacology, University of Nevada, Reno, Nevada, United States of America
Basant Patel
Current address: Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Medak District, India
Affiliation: Department of Pharmacology, University of Nevada, Reno, Nevada, United States of America
ORCID http://orcid.org/0000-0001-9465-4803
Alex Tietsort
Affiliation: Department of Biochemistry and Molecular Biology, University of Nevada, Reno, Nevada, United States of America
Elizabeth M. H. Tank
Affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America
Xingli Li
Affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America
Sami J. Barmada
Affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America
ORCID http://orcid.org/0000-0002-9604-968X
Susan W. Liebman
* E-mail: [email protected]
Affiliation: Department of Pharmacology, University of Nevada, Reno, Nevada, United States of America
ORCID http://orcid.org/0000-0002-5845-4633Abstract
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.
Author summary
Many neurodegenerative diseases are associated with aggregation of specific proteins. Thus we are interested in factors that influence the aggregation and how the...