SUT-2 potentiates tau-induced neurotoxicity in Caenorhabditis elegans
- 9 March 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 18 (10), 1825-1838
- https://doi.org/10.1093/hmg/ddp099
Abstract
Expression of human tau in Caenorhabditis 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 upregulation of SUT-2 protein supporting the connection between SUT-2 and ZYG-12. The human genome encodes three homologs of ZYG-12: HOOK1, HOOK2 and HOOK3. Of these, the human ortholog of SUT-2 (MSUT-2) 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.Keywords
This publication has 59 references indexed in Scilit:
- SUT-1 enables tau-induced neurotoxicity in C . elegansHuman Molecular Genetics, 2007
- Hook2 contributes to aggresome formationBMC Cell Biology, 2007
- A Genomic Screen for Modifiers of Tauopathy Identifies Puromycin-Sensitive Aminopeptidase as an Inhibitor of Tau-Induced NeurodegenerationNeuron, 2006
- Polyglutamine Proteins at the Pathogenic Threshold Display Neuron-Specific Aggregation in a Pan-NeuronalCaenorhabditis elegansModelJournal of Neuroscience, 2006
- Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau SpeciesJournal of Neuroscience, 2006
- FTDP‐17 tau mutations decrease the susceptibility of tau to calpain I digestionFEBS Letters, 1999
- Accelerated filament formation from tau protein with specific FTDP‐17 missense mutationsFEBS Letters, 1999
- Tau is a candidate gene for chromosome 17 frontotemporal dementiaAnnals of Neurology, 1998
- Fatal Familial Insomnia, a Prion Disease with a Mutation at Codon 178 of the Prion Protein GeneNew England Journal of Medicine, 1992
- A novel genetic system to detect protein–protein interactionsNature, 1989