SUT-2 potentiates tau-induced neurotoxicity in Caenorhabditis elegans.
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.
Guthrie
Chris R
CR
Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
Schellenberg
Gerard D
GD
Kraemer
Brian C
BC
D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D039102:Poly(A)-Binding Proteins; D011485:Protein Binding; D016415:Sequence Alignment; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; C054369:MAPT protein, human; D039102:Poly(A)-Binding Proteins; C541940:SUT-2 protein, C elegans; D016875:tau Proteins