Show simple item record

dc.contributor.authorKow, Rebecca L.
dc.contributor.authorSikkema, Carl
dc.contributor.authorWheeler, Jeanna M.
dc.contributor.authorWilkinson, Charles W.
dc.contributor.authorKraemer, Brian C.
dc.date.accessioned2018-02-03T03:39:39Z
dc.date.available2018-02-03T03:39:39Z
dc.date.issued2018-03-01
dc.identifier.citationBiological Psychiatry, Volume 83, Issue 5, 1 March 2018, Pages 438-446. https://doi.org/10.1016/j.biopsych.2017.06.007en_US
dc.identifier.urihttp://hdl.handle.net/1773/40987
dc.description.abstractBACKGROUND: The microtubule-associated protein tau accumulates into toxic aggregates in multiple neurodegenerative diseases. We found previously that loss of D2-family dopamine receptors ameliorated tauopathy in multiple models including a Caenorhabditis elegans model of tauopathy. METHODS: To better understand how loss of D2-family dopamine receptors can ameliorate tau toxicity, we screened a collection of C. elegans mutations in dopamine-related genes (n = 45) for changes in tau transgene–induced behavioral defects. These included many genes responsible for dopamine synthesis, metabolism, and signaling downstream of the D2 receptors. RESULTS: We identified one dopamine synthesis gene, DOPA decarboxylase (DDC), as a suppressor of tau toxicity in tau transgenic worms. Loss of the C. elegans DDC gene, bas-1, ameliorated the behavioral deficits of tau transgenic worms, reduced phosphorylated and detergent-insoluble tau accumulation, and reduced tau-mediated neuron loss. Loss of function in other genes in the dopamine and serotonin synthesis pathways did not alter tau-induced toxicity; however, their function is required for the suppression of tau toxicity by bas-1. Additional loss of D2-family dopamine receptors did not synergize with bas-1 suppression of tauopathy phenotypes. CONCLUSIONS: Loss of the DDC bas-1 reduced tau-induced toxicity in a C. elegans model of tauopathy, while loss of no other dopamine or serotonin synthesis genes tested had this effect. Because loss of activity upstream of DDC could reduce suppression of tau by DDC, this suggests the possibility that loss of DDC suppresses tau via the combined accumulation of dopamine precursor levodopa and serotonin precursor 5-hydroxytryptophan.en_US
dc.description.sponsorshipThis work was supported by Department of Veterans Affairs Merit Review Grant No. 1147891 (to BCK), Bright Focus Foundation Grant No. A2014438S (BCK), and National Institutes of Health National Institute of General Medical Sciences Medical Genetics Postdoctoral Training Program Grant No. T32-GM-007454 (to RLK).en_US
dc.language.isoen_USen_US
dc.publisherElsevieren_US
dc.subjectAromatic amino acid decarboxylase;en_US
dc.subjectDOPA decarboxylase;en_US
dc.subjectDopamineen_US
dc.subjectNeurodegenerationen_US
dc.subjectSerotoninen_US
dc.subjectTauen_US
dc.titleDOPA Decarboxylase Modulates Tau Toxicityen_US
dc.typeArticleen_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record