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Human Molecular Genetics Advance Access published online on March 9, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp099
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Published by Oxford University Press 2009

SUT-2 potentiates tau-induced neurotoxicity in C. elegans

Chris Guthrie1,2, Gerard D. Schellenberg1,2,3 and Brian C. Kraemer1,2,*

1 Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA. 2 Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA 98104, USA. 3 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104-6100

* To whom correspondence should be addressed at: Seattle Veterans Affairs Puget Sound Health Care System, S182, 1660 South Columbian Way, Seattle, WA 98108 Phone (206) 277-3275 Fax (206) 764-2569 Email: kraemerb{at}u.washington.edu

Received November 13, 2008; Revised February 25, 2009; Accepted February 25, 2009

Expression of human tau in C. elegans neurons causes accumulation of aggregated tau leading to neurodegeneration and uncoordinated movement. We used this model of human tauopathy disorders to screen for genes required for tau neurotoxicity. Recessive loss of function mutations in the sut-2 locus suppress the Unc phenotype, tau aggregation, and neurodegenerative changes caused by human tau. We cloned the sut-2 gene and found it encodes a novel sub-type of CCCH zinc finger protein conserved across animal phyla. SUT-2 shares significant identity with the mammalian SUT-2 (MSUT-2). To identify SUT-2 interacting proteins, we conducted a yeast two hybrid screen and found SUT-2 binds to ZYG-12, the sole C. elegans HOOK protein family member. Likewise, SUT-2 binds ZYG-12 in in vitro protein binding assays. Furthermore, loss of ZYG-12 leads to a marked up-regulation of SUT-2 protein supporting the connection between SUT-2 and ZYG-12. The human genome encodes 3 homologs of ZYG-12: HOOK1, HOOK2, and HOOK3. Of these, the human ortholog of SUT-2 (MSUT2) binds only to HOOK2 suggesting the interaction between SUT-2 and HOOK family proteins is conserved across animal phyla. The identification of sut-2 as a gene required for tau neurotoxicity in C. elegans may suggest new neuroprotective strategies capable of arresting tau pathogenesis in tauopathy disorders


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